Virtual Library

Abstract:
The clinical stage is the clinician’s best and final estimate of the extent of the disease prior to the initiation of definitive therapy. As such, the clinical stage creates the foundation for all cancer treatment recommendations. Patients with lung cancer and metastasis to the ipsilateral mediastinal and/or subcarinal lymph node(s) (LN) have a nodal descriptor of N2. Such N2 metastasis reflects a biologically advanced disease with spread beyond the primary tumor in the lung itself. In the forthcoming eighth addition of the TNM classification for lung cancer, the current (7th edition) nodal descriptors and location for both clinical and pathological nodal status (N0 to N3) adequately predict prognosis. Although for lung cancer, nodal status is based on the anatomic location of the involved node, and not on the number of metastatic lymph nodes, future staging models could assess the number of involved nodes and location.(1) Determination of metastases to mediastinal lymph nodes constitutes a critical point in staging and treatment recommendations. Computed tomography and FDG-PET + CT scans are helpful to guide treatment decisions; invasive staging is still recommended to confirm mediastinal nodal involvement. (2) (3) (4) Invasive staging for diagnosis of N2 LN includes cervical mediastinoscopy (CME) or mediastinotomy (Chamberlain’s procedure), endoscopic bronchial ultrasound (EBUS), or esophageal ultrasound (EUS). The use of CME regardless of radiographic evidence of nodal involvement (“routine mediastinoscopy”) is not a cost effective approach, and adds little to the accuracy of staging in patients with an adequate noninvasive preoperative evaluation. (5) Endobronchial ultrasound combined with mediastinoscopy (2;4) can be effective. VATS techniques can evaluate enlarged level 5 or 6 lymph nodes, and as well, enlarged level 8 or 9 or low level 7 lymph nodes. Esophageal ultrasound (EUS) guided aspiration can be used for level 7 and AP window LN Patients with clinically early stage NSCLC (cStage I or II), who have complete resection (R0) and subsequently identified microscopic or occult N2 metastases, represent a biologically favorable subset with improved survival following adjuvant therapy. Surgery alone for cStage IIIA (N2) lung cancer is infrequently performed however, selected patients may benefit from a multidisciplinary approach to treatment which include local and systemic components. (6). Definitive concurrent chemoradiotherapy is commonly recommended for N2 disease given the identifiable locally advanced NSCLC and likely occult systemic metastases. . Induction chemoradiotherapy has been evaluated for treatment of clinical stage IIIA (N2) NSCLC. (7;8) In these two phase III trials, surgery did not provide an overall survival benefit; however, in an exploratory analysis, induction therapy followed by lobectomy had improved survival. Multidisciplinary team discussions for individual patients are essential to optimize benefits of treatment. In selected resectable IIIA NSCLC patients, induction chemoradiotherapy followed by resection is an alternative treatment to chemoradiotherapy alone. (6) The Society of Thoracic Surgery National General Thoracic Surgery Database evaluated identified only 3319 patient with cStage IIIA (N2) NSCLC who underwent resection between 2002 and 2012. (9) Patients were >65 years of age and only 46% were treated with induction therapy. 93% had FDG PET scans, and 51% were coded as having undergone invasive mediastinal staging. Nodal over-staging occurred in 43% of patients. Lobectomy was the most common procedure (69%). The unadjusted 5 year survival following induction therapy was 35%. Selection of patients for resection may depend on the number of ipsilateral LN stations involved, and the ability of induction therapy to create a clinical post-induction yN0 nodal status. Endobronchial ultrasound (EBUS) is used initially to diagnosis ipsilateral LN metastasis and exclude contralateral metastasis. Following induction therapy, repeat EBUS may confirm yN0 status of the previously involved LN, and be validated by cervical mediastinoscopy. The surgeon must answer this question for each patient with N2 disease: When does resection following induction therapy consistently provide better survival than definitive C+RT? Large pragmatic clinical trials may facilitate new knowledge in this area. Regardless of approach (open or minimally invasive techniques), a mediastinal lymph node dissection is recommended. A recent study utilizing the National Cancer Database from the American College of Surgeons Commission on Cancer, demonstrated that with Stage I NSCLC better survival was associated with resecting 10 or more lymph nodes to optimally confirm stage I status.(10) Although this is not a therapeutic intervention, it emphasizes the need for mediastinal lymph node dissection to ensure accuracy by decreasing variability in the mediastinal dissection, and optimizing the accuracy of the pathologic staging. Reference List (1) Asamura H, Chansky K, Crowley J, Goldstraw P, Rusch VW, Vansteenkiste JF, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer. J Thorac Oncol 2015 Dec;10(12):1675-84. (2) Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, et al. Methods for staging non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):211S-50S. (3) Stamatis G. Staging of lung cancer: the role of noninvasive, minimally invasive and invasive techniques. European Respiratory Journal 2015 Aug;46(2):521-31. (4) Detterbeck FC, Postmus PE, Tanoue LT. The stage classification of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):191S-210S. (5) Fernandez FG, Kozower BD, Crabtree TD, Force SD, Lau C, Pickens A, et al. Utility of mediastinoscopy in clinical stage I lung cancers at risk for occult mediastinal nodal metastases. J Thorac Cardiovasc Surg 2015;149(1):35-41. (6) Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA, et al. Treatment of stage III non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013 May;143(5:Suppl):314S-40S. (7) Albain KS, Swann RS, Rusch VW, Turrisi AT, III, Shepherd FA, Smith C, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 2009 Aug 1;374(9687):379-86. (8) van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007 Mar 21;99(6):442-50. (9) Boffa D, Fernandez FG, Kim S, Kosinski A, Onaitis MW, Cowper P, et al. Surgically Managed Clinical Stage IIIA-Clinical N2 Lung Cancer in The Society of Thoracic Surgeons Database. Ann Thorac Surg 2017 Aug;104(2):395-403. (10) Samayoa AX, Pezzi TA, Pezzi CM, Greer GE, Asai M, Kulkarni N, et al. Rationale for a Minimum Number of Lymph Nodes Removed with Non-Small Cell Lung Cancer Resection: Correlating the Number of Nodes Removed with Survival in 98,970 Patients. Annals of Surgical Oncology , 2016 23, Suppl 5:1005-1011.

Abstract:
The unique location of Pancoast tumors makes complete resection challenging and usually includes the upper lobe, involved chest wall with or without the subclavian vessels, portions of the vertebral column and T1 nerve root, and dorsal sympathetic chain. Several approaches are used depending on tumor location. Posterior Approach The patient is positioned in the lateral decubitus position, rotated slightly anteriorly to expose the paravertebral region. The chest is explored via a posterolateral thoracotomy in the 5[th] intercostal space. If the tumor appears resectable, the incision is extended to the base of the neck posteriorly and around the anterior border of the scapula anteriorly. The scapula is elevated with an internal mammary retractor. The scalene muscles are detached from the first and second ribs. Involved ribs are divided anteriorly. Dissection is carried along the superior border of the first rib in the subperiosteal plane. The erector spinae muscles are retracted off the thoracic spine to expose the costovertebral gutter. The transverse processes and rib heads are resected en-bloc at the lateral border of the facet joint. The chest wall is retracted anteriorly, and the intercostal nerves ligated before division to prevent cerebrospinal fluid leak. Thoracic nerve roots below T1 are transected without neurologic sequelae. Since the T1 nerve root provides motor innervation to the hand, it is ligated only in cases of tumor invasion. Division of the C8 nerve root will result in permanent arm/hand paralysis. The detached chest wall is allowed to fall into the chest cavity and an upper lobectomy and lymph node dissection is completed. Reconstruction of the chest wall is necessary when the defect is larger than the first three ribs and can be performed with a 2 mm thick PTFE patch. Tumors Involving the Vertebral Bodies and Epidural Region Vertebral body invasion by Pancoast tumors no longer a contraindication to surgical resection because of contemporary spine instrumentation. With multimodality therapy, T4 lesions with vertebral body or epidural extension can be resected with curative intent. We use spine MRI to divide tumors into four classes, A-D, based on the degree of spinal column and neural tube involvement. Class A and B tumors are T3 lesions amenable to complete R0 resection. Class C and D tumors are T4 lesions not amenable to en-bloc resection but can still be completely resected. Class C tumors extend into the neural foramina with limited or no vertebral body involvement but have unilateral epidural compression. Class D tumors involve the vertebral column, either the vertebral body and/or lamina with or without epidural compression. Class A, B and some class C tumors are approached through a posterolateral thoracotomy. A high-speed drill is used to remove involved vertebral bodies. The posterior longitudinal ligament is removed and provides a margin on the anterior dura. The disc spaces adjacent to the tumor are exenterated in order to aid in spinal fixation. Anterior reconstruction alone is sufficient for resections of 1-2 vertebral bodies. Autologous bone from the iliac crest or non-diseased rib, allograft fibula, methymethacrylate with Steinman pins, or corpectomy cages can all be used for reconstruction. Patients requiring any degree of epidural decompression in the upper thoracic spine undergo combined posterior and anterior approach. Long segment posterolateral spinal instrumentation and fusion avoids the development of debilitating deformity. Class D tumors involving the posterior elements (spinous process, laminae, and pedicles) are also resected through a combined posterior/anterior approach. Patients are first positioned prone and a posterior midline incision made. The involved areas of the spinous process, laminae, and pedicles are resected. Epidural tumor is dissected off the dura and a multilevel resection of affected nerve roots done. Posterior fixation is accomplished in order to maintain coronal and sagittal stability. Muscle flap rotation by a plastic surgeon can be done to reduce the risk of skin breakdown and infection of the spine hardware. The incision is then closed, the patient turned to the lateral decubitus position, a posterolateral thoracotomy performed, and the lung and chest wall resection completed. Anterior Approaches Pancoast tumors involving the subclavian vessels are best approached anteriorly, using the anterior transcervical approach originally described by Dartevelle and modified by others. The patient is positioned supine with the neck hyperextended and the head turned to the opposite side of the lesion. An inverted L-shaped incision is carried down the anterior border of the sternocleidomastoid muscle and extended below the clavicle to the level of the second intercostal space, then turned horizontally following a parallel line below the clavicle to the deltopectoral groove. The sternal attachment of the sternocleidomastoid is divided along with the insertion of the pectoralis major. The scalene fat pad and lymph nodes are excised. If the tumor is resectable, the upper part of the manubrium is divided and the incision carried into the second intercostal space via an L-shaped incision. The involved section of the subclavian vein is resected but not reconstructed. The anterior scalene muscle is divided at its insertion onto the first rib. The phrenic nerve is preserved. The subclavian artery is resected and reconstructed with a 8 or 10 mm PTFE graft. The middle scalene muscle is detached from the first rib to expose the C8 and T1 nerve roots. The ipsilateral prevertebral muscles and paravertebral sympathetic chain and stellate ganglion are resected off the anterior aspect of the vertebral bodies of C7 and T1. TheT1 nerve root is commonly divided just lateral to the T1 intervertebral foramen. The anterolateral arch of the first rib is divided at the costochondral junction and the second rib is divided at its midpoint. The third rib is dissected on its superior border in a posterior direction toward the costovertebral angle and the first two through three ribs are disarticulated from the transverse processes. From this cavity, an upper lobectomy is completed. If exposure for the lobectomy and chest wall resection is inadequate, the anterior incision is closed, the patient turned into the lateral decubitus position and the rest of the resection performed via a posterolateral thoracotomy

Abstract:
In recent years, the number of early stage lung cancers has enormously increased mainly due to frequent use of chest CT in routine practice or screening purpose. Both curability and non-inavasiveness are required especially for such early disease. Increased number of VATS lobectomy and sublobar resection for selected patients is the international trend in such situation. Diagnosis: Retrospective data revealed that the sensitivity of conventional bronchoscopic examination for peripheral cancer < 2cm is only 34%. The combination of Virtual bronchoscopic navigation and EBUS guide-sheath has demonstrated the improved sensitivity, thus this new combination strategy should be necessary for differential diagnosis of small cancers detected by chest CT[1)]. Surgical procedure: A total of 38000 lung cancers were resected in Japan in 2013 and 70% of surgeries were video-assisted[2)]. Segmentectomy has been performed intentionally mainly for lung cancer 2cm or less in diameter. Several comparative studies between lobectomy and segmentectomy for tumors < 2cm showed no significant difference in survival[3)]. Recently, segmentectomy is selected based on the size and high resolution CT (HRCT) findings of the tumor. The proportion of consolidation diameter to tumor diameter correlates with biological malignancy and the establishment of robust image criteria predicting non-invasive cancer is desirable to find candidates for segmentectomy. The Japan Clinical Oncology Group (JCOG) conducted a prospective study to recognize the relationship between HRCT finding and pathological non-invasiveness in clicical stage IA cancer (JCOG0201)[4)]. This study revealed that adenocarcinoma <2.0 cm with <0.25 consolidation to the maximum tumor diameter showed pathological non-invasiveness in 98.7% and this criterion could be used to predict early lung cancer preoperatively[5)]. Based on the result of JCOG0201, two prospective studies were performed and finished recruitment, phase II trial of wide wedge resection for radiological non-invasive adenocarcinoma (tumor diameter 2cm or less and consolidationratio<0.25) (JCOG0804) and randomised phase III trial for radiological invasive adenocarcinoma (tumor diameter 2cm or less and consolidation ratio>0.25) to evaluate non-inferiority in OS of segmentectomy compared to lobectomy (JCOG0802)[6)]. The indication of segmentectomy will be demonstrated by the results of these studies. Clinical research: PET-CT has been routinely used for clinical staging and the standardized uptake value (SUV) of the main tumor is recognized to be as a predictor of the clinicopathological characteristics and prognosis. Analyses of 610 resected stage IA adecocarcinoma showed that maxSUV and GGO ratio cutoffs to predict recurrence were 2.9 and 25%, respectively. They were also related to nodal metastasis, histological tumor invasiveness and recurrence. The 5-year RFS of cases with maxSUV <2.9 (n=456) was 95%, while cases with maxSUV>2.9 (n=154), 72% (p<0.001)[7)]. Our result showed that maxSUV cutoff of possibility for recurrence was 2.6 in adenocarcinoma, which was also related to nodal metastasis and histological tumor invasiveness. The 3-year relapse-free survival was 99%/78% (maxSUV lower/higher than 2.6) and following multivariate analysis, pathological nodal status and SUVmax were found to be independent predictive factors for relapse-free survival. Surgical management of early stage lung cancer should be selected based on the tumor size and consolidation ratio on HRCT. The results of RCTs will demonstrate the indication of sublobar resection in near future. Further analysis is encouraged for the evaluation of biological aggressiveness in each case[8)]. References Asano F, Shinagawa N, Ishida T, et al. Virtual bronchoscopic navigation combined with ultrathin bronchoscopy. A randomized clinical trial. Am J Respir Crit Care Med 2013; 188:327-333 Committee for Scientific Affairs The Japanese Association for Thoracic Surgery, Thoracic and cardiovascular surgery in Japan during 2013 : Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg.2015;63:670-701. Okada M, Koike T, Higashiyama M, et al. Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study. J Thorac Cardiovasc Surg. 2006; 132: 769-775 Suzuki K, Koike T, Asakawa T, et al.: A prospective radiological study of thin-section computed tomography to predict pathological noninvasiveness in peripheral clinical IA lung cancer (Japan Clinical Oncology Group 0201). J Thorac Oncol 2011;6:751-756 Asamura H, Hishida T, Suzuki K, et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201 J Thorac Cardiovasc Surg 2013;146:24-30 Nakamura K, Saji H, Nakajima R, et.al. A Phase III Randomized Trial of Lobectomy Versus Limited Resection for Small-sized Peripheral Non-small Cell Lung Cancer (JCOG0802/WJOG4607L) Jpn J Clin Oncol 2010;40:271–274 Uehara H, Tsutani Y, Okumura S, et al. Prognostic Role of Positron Emission Tomographyand High-Resolution Computed Tomography in Clinical Stage IA Lung Adenocarcinoma Ann Thorac Surg 2013;96:1958–1965 Tsutani Y, Miyata Y, Nakayama H,et al.. Sublobar resection for lung adenocarcinoma meeting node-negative criteria on preoperative imaging. The Annals of thoracic surgery. 2014;97:1701-1707

Abstract:
During the last two-three decades the surgical approach for the treatment of lung cancer had significantly changed. Compared to the traditional posterolateral thoracothomy the introduction and diffusion of a more conservative muscle sparing lateral thoracothomy has shown a first change to lesser trauma for patients, but only with the advent of mininvasive surgery we have witnessed the real change in terms of improving the quality of life and reducing perioperative pain (1). According to some review articles (2) not only perioperative outcome was improved with MIS compared to thoracotomy but also advantages in terms of oncological outcome have been reported even if it is possible that some selection bias could have played a role in the review results. Many studies have confirmed the benefits for the patients treated with MIS compared to open including reduced pain, complications, blood trasfusions and postoperative stay, and improved quality of life, ahestetic and functional results (3). Different technique have been described with different number of small incisions but all have in common that no rib spreading is performed and the dissection is done looking at the monitor. The most common videothoracoscopic techniques are: a. the Cophenaghen approach with an anterior incision of 4-6 cm in the IV intercostal space and 2 more trocars is characterised by an anterior to posterior approach to the mediastinum. This technique has been described by Heine Hansen and by Mc Kenna (4); b. the posterior approach of the Edinburgh school has been described by William Walker and reproduces the posterior approach to the hylum similar to that of the posterolateral thoracothomy (5). In this technique the utility incision is posterior, in the auscultatory triangle and usually two or three additional ports are used; c. the single port described by Gaetano Rocco and Diego Gonzales Riva with a single incision of 4-8 cm usually in the V intercostal space through which the tools and the camera are inserted (6). More recently new approaches has been described including the microlobectomy and the subxhifoid approach. Both techniques are aimed to reduce the pain of the intercostal nerve injury by avoiding the utility incision in the intercostal space. Despite all these advantages for the patients the manual vats has been embraced by a minority of thoracic surgeons and the diffusion has been very slow mainly due to technical difficulties, like the limited visual information, limited freedom of movement, unstable camera platform and poor ergonomics, and doubts on oncological radicality. To overcome videothoracoscopic technical limitations, the micromechanic and robotic sophisticated technology has been introduced with the robotic surgical systems. Natural movements of the surgeon’s hands are translated into precise instrument movements inside the patient with tremor filtration. Three dimensional view offers a visual magnification that compensate the absence of haptic feedback. The robotic surgical system is the result of a long process of development aimed at producing a natural extension of the surgeon’s eyes and hands via the intermediation of a computer. In this way, the ease of movement obtained with open surgery is summated with the advantages of the minimally invasive technique. Since 2002, when the first robotic system for surgery was introduced, robot-assisted thoracic surgery (RATS) has been adopted by an increasing number of centres around the world, and today is used in ~10% of lobectomies in the US (7, 8). Two different techniques have been described in robotic thoracic surgery, the complete portal robotic lobectomy or segmentectomy (CPRL or CPRS) maynly used by surgeons of North American, characterised by 3-4 arms technique, CO2 insufflation, posterior to anterior hilar dissection and a specimen extraction incision at the end of the procedure (9); and the Robotic Assisted Thoracoscopic Surgery (RATS), characterized by a 4-arms approach, a utility incision since the beginning, no routine CO2 insufflation and anterior to posterior hilar dissection (10). To date, no randomized trials have reported comparative data on RATS vs. VATS or thoracotomy for lung cancer. Retrospective analysis comparing RATS vs. thoracotomy have revealed advantages for the RATS approach, especially shorter hospital stays and a lower complication rate but when compared to VATS, RATS produces similar or only slightly better results, the two being minimally invasive techniques with no need for rib separation. A few studies have reported RATS to be safer than VATS, with less conversions for bleeding, less complications and lengths of stay; in others, it was associated with lower postoperative consumption of pain killers and quicker return of patients to normal activity. In addition, lymph-node upstaging has been shown to be higher with RATS than with VATS, with a similar rate as thoracotomy. The main disadvantage of RATS is the higher costs of instrumentation and surgical kits. Nevertheless, the future will probably see reductions in the costs of robotics and improvements in the instrumentation, integration with 3D imaging to improve virtual reality, and more patients benefitting from minimally invasive procedures for lung malignancies. References 1. Demmy TL, Curtis JJ. Minimally invasive lobectomy directed toward frail and high-risk patients a case-control study. Ann Thorac Surg 1999;68:194-200. 2. Whitson BA, et al. Thoracoscopic versus thoracotomy approaches to lobectomy: differential impairment of cellular immunity. Ann Thorac Surg 2008;86:1735-44. 3. Bendixen M, et al. Postoperative pain and quality of life after lobectomy via video-assisted thoracoscopic surgery or anterolateral thoracotomy for early stage lung cancer: a randomised controlled trial. Lancet Oncol. 2016;17:836-44. 4. Hansen HJ, et al. Video-assisted thoracoscopic surgery (VATS) lobectomy using a standardized anterior approach. Surg Endosc. 2011;25:1263-9. 5. Walker WS, et al. Thoracoscopic pulmonary lobectomy. Early operative experience and preliminary clinical results. J Thorac Cardiovasc Surg. 1993;106:1111-7. 6. Gonzalez-Rivas D, et al. Uniportal video-assisted thoracoscopic bronchovascular, tracheal and carinal sleeve resections†. Eur J Cardiothorac Surg 2016;49 Suppl 1:i6-16. 7. Park BJ, et al. Robotic assistance for video-assisted thoracic surgical lobectomy: technique and initial results. J Thorac Cardiovasc Surg 2006;131:54-9. 8. Cerfolio RJ, et al. Initial consecutive experience of completely portal robotic pulmonary resection with 4 arms. J Thorac Cardiovasc Surg 2011;142:740-6. 9. Dylewski MR, et al. Pulmonary resection using a total endoscopic robotic video-assisted approach. Semin Thorac Cardiovasc Surg 2011;23:36-42. 10. Veronesi G, et al. Four-arm robotic lobectomy for the treatment of early-stage lung cancer. J Thorac Cardiovasc Surg 2010;140:19-25.

Abstract:
High risk lung cancer patients represent a challenge in thoracic oncology, they are often related to heavy smoke habit with increased cardiovascular or respiratory diseases that prevents for getting optimal results in their lung cancer treatment. In the other hand it is widely accepted that lobectomy and lymphadenectomy is the standard treatment for younger patients with adequate cardiopulmonary function, specially in solid lung cancer patients (1). High risk patients with early stage lung cancer, often undergo sublobar resections, regardless of histology or tumor size, which increases the risk of local recurrence and may decrease long-term survival. However, a significant group of these patients have a good prognosis, either because their histology or tumor size are favorable, they present slow growing tumors or because they can undergo anatomical sublobar resections and a lymphadenectomy that provides an adequate disease control. In patients without respiratory or cardiovascular impairement it is accepted that sublobar resections have the same possibility of controlling the disease than lobectomy for ground glass opacity lesions, partially solid lesions (<50%) or with invasion area less than 5mm (2,3,4). The biggest problem appears in high-risk patients with solid lesions, in whom sublobar resections have not demonstrated the same oncological performance compared to lobectomy. This group will face the dilemma of decreasing operative morbimortality and the risk of postoperative respiratory disability versus decreased global and disease-free survival (5). Reports and our own expeience with the treatment of T1 and T2 patients with segmentectomies and wedge resections suggests that it is appropriate to try these patients with economical resections to improve the quality of life and survival in a group of patients whose survival curve does not depend only on cancer, but it is also important the competitive causes of mortality (ex. cardiovascular disease, pulmonary fibrosis, emphysema) (5). In our group, we evaluate cardiovascular risk with echocardiography and provocative test for myocardial ischemia, preferably exercise stress test. Respiratory risk is evaluated with spirometry, DLCO and cardiopulmonary exercise testing (peak VO2 and ventilatory equivalent VE/VCO2) (6,7). If ppoFEV1 <60%, ppoDLCO <60%, V02 <10-15ml/kg/min and/or CO2 equivalent >35, values that show that the patient is high-risk or inoperable, we incorporate the patient to an exercise training program. Our protocol considers 1-1.5 hours/day of training, with progressive load to improve muscular strength, cardiovascular and respiratory capacity, associated with full medical treatment (LABA/LAMA inhalers plus inhaled and eventually systemic corticosteroids). After completing the training period, the patient is reevaluated and the treatment plan is defined: 1.- If he leaves the high-risk group (VO2 >15ml/kg/min with VE/VCO2 <35), he will receive standard oncological surgery, according to tumor size and radiological/histological findings (TNM, GGO vs solid component, invasion). 2.- If the surgical contraindication persists (VO2 <10ml/kg/min with VE/VCO2 >35), we prefer non-surgical treatments (like SBRT). In our institution, less than 5% of patients that enter the training program remain inoperable. 3.- If the patient persists in the high or moderate-risk group (VO2 10-15ml/kg/min with VE/VCO2 <35), we prefer sublobar resections. In patients where the tumor is pure GGO or predominantly GGO (<50% solid) and measure less than 2 cms, we perform a VATS wide wedge resection plus hilar and mediastinal sampling. Frozen section must confirm that less than 50% is invasive or invasion area is smaller than 5mm. Margins should be larger than 1cm to persevere with wedge resection. If these requirements are not met: solid tumors larger than 10mm or mostly solid/GGO tumors, or GGO tumors greater than 2 cm with >25% solid, or has an invasive component larger than 5mm, we perform an anatomic segmental resection, by VATS or thoracotomy, associated with hilar and mediastinal lymphadenectomy (2,8,9,10). 4.- Even in larger tumors, we will attempt segmental resection in high-risk patients. We consider that although the risk of local recurrence is high, the lower morbidity and mortality rate of sublobar resections justifies this approach in high-risk patients. We believe that a sublobar resection with margins larger than 1 cm, grant better quality of life than a patient who becomes oxygen dependent, dies in the postoperative period or has not been resected due to the impossibility of lobectomy. In our institution, we have a prospective registry of morbidity that allows us to evaluate M&M rate and the relation with VO2 in patients with lobar and sublobar resections (5,9).(Fig1) Finally, in those patients with solid tumors and lymphovascular invasion, that are staged as clinically an pathological N0, the problem is that the intralobar lymph nodes are not completely accessible or evaluable. This implies that actually the N1 barrier is not adequately studied with sublobar resections, especially in those patients undergoing a training program and become candidates to wedge or even anatomical segmental resections as a treatment choise. This lack of information may be acceptable in AIS or MIA tumors, but constitute a greater risk in patients with solid or partially solid tumors, and even greater risk in those with lymphovascular invasion in the paraffin section. Should we consider these patients as potential N1 and add treatment to avoid the risk of relapse? There is no evidence to support this approach yet, but we feel it should be considered. References 1.- De Zoysa MK et al. Is limited pulmonary resection equivalent to lobectomy for surgical management of stage I non-small-cell lung cancer? Interactive CardioVascular and Thoracic Surgery 14(2012) 816-20 2.-Asamura H et al. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30 3.- Sakurai H, Asamura H. Sublobar resection for early stage lung cancer. Transl Lung Cancer Res 2014;3(3):164-172 4.- Suzuki K, Asamura H et al. “Early” peripheral lung cancer: prognostic significance of Ground Glass Opacity on thin-section computed tomographic scan. Ann thorac Surg 2002;74:1635-9 5.- Nakamura H et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small-cell lung cancer. 2011 Apr;59(3):137-41. 6.- Shafiek et al. Risk of postoperative complications in chronic obstructive lung disease patients considered fit for lung surgery: beyond oxygen consumption. Eur J Cardiothorac Surg 2016; doi:10/1093/ejcts/ezw104 7.- Salati M, Brunelli A. Risk stratification in lung resection. Curr Surg Rep. 2016; 4:37 8.- Hattori A et al. Prognostic impact of the findings on thin section computed tomography in patients with subcentimetric non small cell lung cancer. JTO 2017;12(6):954-962 9.- Valenzuela R et al. Long term survival of lung cancer in Chile. JTO2017;12(1):S745-S746 10.-Aokage K et al. Limited resection for early-stage non-small cell lung cancer as function-preserving radical surgery: a review. Jpn J Clin Oncol,2017,47(1):7-11 Figure 1 Fig 1: Survival in Resected NSCLC Lung Cancer by peak VO2, adjusted by TNM Patients with peak VO2 less than 15 ml/kg/min present a worse survival. Data obtained in a serie of 55 patients in the last preoperative evaluation, after training. Clinica Santa María, Santiago, Chile

Abstract:
Salvage thoracic surgery has become an increasingly common indication in patients with lung cancer (1). In principle, three different indicative fields of salvage surgery in patients with lung cancer can be distinguished: a) the surgical resection of a persistent or recurring primary lung tumor after stereotactic radiotherapy, b) salvage lung resection after definitive chemoradiation therapy for Stage III non-small-cell lung cancer, or c) palliative surgery in cases with e. g. massive haemoptyses or bronchial obstruction with treatment-resistant retention pneumonia. Common to all indications is that they are always individual case decisions. The published series are all retrospective, comprise only a small number of patients and refer to a long period at a single institution. All studies show that these operations are often surgically challenging and demanding and require careful consideration of individual patient related factors. The presentation will provide an overview of the current literature, and will discuss own clinical experiences from selected cases. SBRT is an increasingly used modality in patients with stage I lung cancer. Whereas in the past SBRT was typically considered an alternative to surgery for patients unfit or at high risk for surgery, the modality is now being used more often also for healthier, potentially operable patients. In a recent study from MD Anderson Cancer Center, Antonoff and colleagues presented a retrospective analysis of the largest series of pulmonary resections after local SBRT failure reported to date, along with a cumulative review that incorporates all patients who have been previously reported. (2) They demonstrated that resection after local failure of SBRT in highly select individuals is feasible and safe, and has an overall acceptable morbidity and mortality, albeit higher than what is typically observed in nonirradiated patients. It is of note that in their series the majority (73%) of patients underwent lobectomy, and only 24% of patients underwent sublobar resections. In considering salvage resection, the authors recommend careful consideration of the patient’s performance status and the likely extent of required resection, to be discussed thoughtfully both with the patient and in a multidisciplinary tumor board setting. Local recurrence is observed in 20% - 35% of patients after definitive chemoradiation therapy for Stage III non-small-cell lung cancer. In selected cases salvage surgery may be considered. A recent study from Italy identified 35 cases that underwent salvage surgery after definitive chemoradiation therapy for locally advanced non–small cell lung cancer over a period of 10 years, representing 1.2% of all lung resections for lung cancer performed at their institution. (3) The authors showed acceptable postoperative survival (2- and 3-year OS was 39% and 33%, respectively) and complication rates (25.7% of both minor and major complications). Another recent study from the Netherlands reported on 15 patients that underwent salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiation therapy for locally advanced non-small cell lung cancer. The authors concluded that selected patients with locoregional recurrence or persistent tumor after high dose chemoradiation therapy, can undergo salvage surgery with acceptable morbidity and mortality, even when a pneumonectomy is required (4). Factors that might have contributed to their favourable results included adequate pre-operative staging, ability to obtain an R0 resection and a good performance status. Based on the favourable results, the authors emphasised that medically operable patients presenting with locoregional recurrence or persistent tumor after definitive chemoradiation therapy for NSCLC, should have all treatment options reviewed in an experienced multidisciplinary tumor board. In conclusion, salvage surgery after stereotactic radiotherapy or after definitive chemoradiation therapy for Stage III non-small-cell lung cancer has become a new challenge for thoracic surgeons. References: 1. Van Schil PE. Salvage surgery after stereotactic radiotherapy: a new challenge for thoracic surgeons. J Thorac Oncol; 2010. p. 1881-2. 2. Antonoff MB, Correa AM, Sepesi B, Nguyen QN, Walsh GL, Swisher SG, Vaporciyan AA, Mehran RJ, Hofstetter WL, and Rice DC. Salvage pulmonary resection after stereotactic body radiotherapy: A feasible and safe option for local failure in selected patients. J Thorac Cardiovasc Surg; 2017;154(2):689-699. 3. Casiraghi M, Maisonneuve P, Piperno G, Bellini R, Brambilla D, Petrella F, Marinis FD, and Spaggiari L. Salvage Surgery After Definitive Chemoradiotherapy for Non–small Cell Lung Cancer. Seminars in Thoracic and Cardiovascular Surgery. Elsevier BV; 2017;. 4. Dickhoff C, Dahele M, Paul MA, van de Ven PM, de Langen AJ, Senan S, Smit EF, and Hartemink KJ. Salvage surgery for locoregional recurrence or persistent tumor after high dose chemoradiotherapy for locally advanced non-small cell lung cancer. Lung Cancer; 2016;94:108-13.

Abstract:
It is required to improve patient-physician communication and that patients be offered participation in informed decisions regarding their care ethically in the context of serious and life-limiting illnesses, citing effects of good communication on quality of care and life. Many patients with advanced cancer and caregivers seek empathetic communication from physicians. Inadequate communication about prognosis and treatment choices is common and is associated with unrealistic patient expectations regarding curability, provision of aggressive treatment that is not concordant with patients’ wishes and enrollment in hospice too late to deliver discernable benefit. Conversations related advance directive and advance care planning typically do not happen, or happen in hospital shortly before a patient’s death. In order to complete advance directives and prepare an appropriate advance planning, it is necessary to promote physicians’ empathic communication. Therefore, we developed the 2-day communication skills training (CST) for physicians based on patient preferences and confirmed the effectiveness for both patients’ psychological distress and physicians’ empathetic communication behaviors through a randomized controlled trial. After confirming the effectiveness at RCT, CST was conducted for doctors nationwide as a clinical implementation as a consignment project by the Ministry of Health, Labor and Welfare. Meanwhile, we developed question asking prompt list (QPL) for patients who were newly advanced lung and gastrointestinal cancer use in consultations and confirmed the usefulness through a randomized controlled trial. However, the QPL did not affect the number of actual question from the patient to the physician. It was needed to develop apamphletn intervention with QPL. Furthermore, the evaluation of caregivers is also needed. This presentation aims to determine the effectiveness of an integrated communication support program for promoting empathetic communication between rapidly progressive cancer patients, families and doctors, and to estimate the intervention effects on distress and QOL of patients and caregivers, faith in their physicians. These evidence of an effective intervention to promote communication and decision-making process based patients’ values and preferences between patients, caregivers and physicians with reducing physicians’ burden will be created. Based on the results, we will reflect clinical guideline regarding communication between patients and physicians in cancer care and develop a train-the-trainer workshop program with related academic society. It is also expected that providing supportive therapy at cancer hospitals will be standardized and subsequently the quality of life of cancer patients will be improved.

Abstract:
Patients with advanced, incurable cancer, and also their family members, typically struggle between hopes to have long lives or even get cured and the concious, unconcious or denied reality of limited life time due to cancer. This struggle becomes more pronounced in modern oncology, making predictions of response to anticancer treatments or survival increasingly difficult. Adressing existential issues and uncertainties is an often feared theme for cancer clinicians (doctors, nurses, other professionals) in clinical practice: concerns about destroying hope, hesitation about own professional role (e.g., authentic, paternalistic, servant for patients autonomy), doubts about involvement of family members, incertitude about decisional processes on anticancer treatments, or prudence on patients emotional condition (e.g., stress, trauma, anxiety, depression, anger) may constitute real challenges. Adequate communication skills including empathetic communication and concepts of shared decision making are necessary, but often not suffcient to perform as an accountable, understanding, educating, empowering, self-reflective, and competent clinician guiding patients and families to address the reality of limited live time, death, dying and bereavement. Preparation for illness-deterioration and end-of-life encompasses continuous engagement in a) patients illness understanding (e.g., causes and impact of pain, fatigue, or cachexia); b) decisional processes for or against anticancer treatments (e.g., concrete goals, significance of burdens, characterization of patients values and expressed definition of own quality-of-life); c) worst and best time range scenarios of life expectancy (never say a concrete mean estimate !) These communicative, educational and counselling interventions are part of early integrated palliative care, supported by high quality evidence to improve patients quality-of-life and symptoms. To integrate palliative care early services may adapt the name (supportive) but not the content. Advanced care plans (ACP) shall include most relevant elements to prepare for the end-of-life period, but often they are limited to power of attorney and life-sustaining treatment choices (e.g., POLST, Advanced Directives); evidence suggests that such limited processes may not alleviate existential distress, but still are important. ACP shall encompass a structured process delivered in several encounters of patient and family members with cancer clinicians, built on a trustful relationship invigorated in good decisions, patients values and life concept including spiritual aspects and patients and families’ adequate illness- and prognosis understanding. Evidence supports that ACP do not deteriorate hope and that even in cultures not used to ACP patients welcome them. Key elements of ACP encompass patients’ life values, expressed understanding and preferences of management of typical complications and disease deteriorations, concrete professional support (nurses, specialized palliative care nurses, physicians, other professionals, 24/7), timeschedule of family members offering support, preferred place of death, adressing premortal grief with important people, adressing premortal preparation for postmortal roles, preferences for funeral arrangments, legacy work, finish business including legal & financial issues and words of love, excuse, forgiveness and love, use time left conciously, prepare for prolonged live and lazarus effects. To engage in ACP clinicians may self-reflect about own accountability to have an opinion, offered in a humble, reliable, and attentive way. Also clinicians may embrace concepts of healthy denial and the power of the double way: the reality of death and dying together with promises of modern oncology. In summary it is less the issue of what to say, but how to support the process, offer advice and continuous, accountable support.

Abstract:
[Introduction] Dyspnea is one of the most frequent, refractory and distressing symptoms in lung cancer patients. It is reported that dyspnea interferes will to live in terminally ill cancer patients. Palliation of respiratory symptoms is important to improve quality of life (QOL) of cancer patients and their families. [Definition of dyspnea] 'Dyspnea' is defined as 'a subjective experience of breathing discomfort', while 'respiratory failure' is defined objectively as 'pulmonary dysfunction with hypoxia and/or hypercapnia'. Dyspnea and respiratory failure are different entities, and it is shown that the severity of those do not always correlate with each other. [Impact of dyspnea] Dyspnea experience is derived from interactions among physiological, psychological, social, and environmental factors, and may include secondary physiological and behavioral responses. Dyspnea often triggers panic, fear, anxiety, depression, hopelessness, sense of loss of control to patients. Dyspnea is closely associated with fatigue, pain, and depression, and interfering with general activities, mood and enjoyment of life. Dyspnea at rest is also known to correlate with survival, identified as a predictor of poor prognosis in cancer patients. [Clinical Assessment of Dyspnea] As for the assessment of dyspnea, multi-disciplinary team approach and paying attention to patients' own words are important. The assessment should focused on the following three dimensions; 1) quantities (intensity), 2) qualities, 3) symptom impact or burden. Several appropriate scales in each dimensions will be shown in this session. [Management of Dyspnea] Objectives of dyspnea management are to reduce its frequency and severity, minimize its physical, psychological and spiritual distress, and maximize patients' function and QOL. To achieve these goals, the first step is to identify all the underlying causes, and when they are reversible and modifiable, to treat them with specific modalities accordingly. It is, therefore, important for oncologists to judge treatability, including adverse effects, and to estimate patients' prognosis accurately. This session will provide the outline of palliative management of dyspnea with focus on pharmacological and non-pharmacological means. [Pharmacological interventions] The Japanese Society for Palliative Medicine (JSPM) published 'Clinical guidelines for respiratory symptoms in cancer patients' in 2016. These guidelines are unique because they are more directly focused on 'dyspnea' management specifically, based on the formal development process for clinical guidelines. Some of the important recommendations will be introduced in this session. *Note: Strength of recommendation: 1 (strong) = recommended, 2 (weak) = suggested. Level of evidence: A (High), B (Moderate), C (Low), D (Very low) 1) Opioids Systemic morphine is recommended to be used (1B). Systemic oxycodone is suggested to be used, as alternative to morphine (2C), while systemic fentanyl is suggested not to be used (2C). Systemic codeine/dihydrocodeine is suggested to be used (2C). 2) Benzodiazepine anti-anxiety Benzodiazepine is suggested to be used in combination with opioid (2C), while it is suggested not to be used alone (2C). 3) Corticosteroid Systemic corticosteroid is suggested to be used in patients with lymphangitis carcinomatosa, superior vena cava syndrome and major airway obstruction (2D). It is, however, suggested not to be used routinely without consideration of dyspnea etiology (2D). [Non-Pharmacological interventions] The effectiveness of non-pharmacological interventions for dyspnea in advanced cancer and non-cancer (mostly chronic obstructive pulmonary disease) has been reported in Cochrane reviews. Interventions supported by good evidence include breathing training, walking aids, and exercise. Those with some evidence include handheld fan, follow-up programs by nurses and acupuncture/ acupressure. [Conclusion] It is difficult to conduct high-quality clinical research on symptom control in advanced cancer patients because of patients' vulnerability as well as the ethical conflict. More clinical researches of good designs need to be conducted in this field, so that standard palliative care may be delivered to all the cancer patients anytime and anywhere, helping them live their own lives with dignity. [References] 1) Chan K, Tse DMW and Sham MMK. Dyspnoea and other respiratory symptoms in palliative care. In: Cherny NI, Fallon MT, Kaasa S, Portenoy RK, Currow DC. Oxford Textbook of Palliative Medicine (5[th] ed). Oxford University Press, 421-434, 2015 2) Yamaguchi T, Goya S, Kohara H. et al. Treatment Recommendations for Respiratory Symptoms in Cancer Patients; Clinical Guideline from the Japanese Society for Palliative Medicine. J Palliat Medicine. 2016, 19(9): 925-935 3) Bausewein C, Booth S, Gysels M, and Higginson I. Non-pharmacological interventions for breathlessness in advanced stages of malignant and non-malignant diseases. Cochrane Database of Syst Rev. CD005623, 2008 4) Non-invasive interventions for improving well-being and quality of life in patients with lung cancer. Cochrane Database of Syst Rev. CD004282, 2011

Abstract:
Lung cancer is the most deadly cancer disease in Denmark, one out of four cancer deaths, is due to lung cancer. 4656 Danes are living with a lung cancer diagnosis in late 2015. There are 4700 new cases each year. This means that lung cancer is responsible for 7,8 % of all deaths in Denmark and 24 % of all cancer deaths.[1]Getting lung cancer has major personal consequences - and major consequences for society. There are rehabilitation services for Danish lung cancer patients, and it has a great potential for improvement. The purpose of lung cancer rehabilitation is to support and assist lung cancer sufferers and their relatives, dealing with the changes in everyday life – including at work – that the disease causes. A lung cancer patient in Denmark meets a nurse in many contexts. Nurses are a necessity for the lung cancer patient and rehabilitation in Denmark. I will present a small sample of the rehabilitation possibilities a lung cancer patient meets in Denmark. My focus is, nurse involvement and whether they have sufficient education for the task. Copenhagen Centre for Cancer and Health provides rehabilitation programs including physical activities, education, and discussion groups or sessions. The rehabilitation programs are for cancer patients living in the City of Copenhagen. A referral from the patient´s GP or hospital department is required in order to participate. There are similar centers in many other cities in Denmark. These centers provide good opportunities for lung cancer patients and rehabilitation. At the Health Care Centre, the lung cancer patient meets nurses.[2] “Well, you know – you have symptoms of something and you come here and tell the others about it and they say “I know just what you are talking about, that is how I´m feeling” – it´s a nice experience and makes me feel that I am all right” - Statement from a man with lung cancer, Copenhagen Centre for Cancer and Health The Danish Cancer Society is the largest disease-fighting organization in Denmark. The organization has more than 430,000 members. They have 3 main work areas in the fight against cancer: #prevention of cancer #giving advice to and supporting cancer patient and their relatives #cancer research. Via this organization, the lung cancer patient can talk to nurses and gets the opportunity to receive information, counseling, social networking and you can be anonymous – if you want to.[3] A Danish lung cancer patient can become a member of the Patient Association for Lung Cancer. It is a nationwide independent association for people with lung cancer and mesothelioma, and their families. You can stay up-to-date on lung cancer treatment, health policy, networking and you can also be a part of a community. You can also help put lung cancer on the agenda. There are 500 members in Denmark.[4] In order for the lung cancer patient's possibilities / conditions to improve, there are many projects in Denmark. The Vision Project - a multidisciplinary working group with professionals across the country and dealing with all aspects of the disease, from surgery to palliative care. Action areas are formulated and concrete initiatives made. In this context, there will be a particular focus on rehabilitation that can improve the life quality of lung cancer patients during and after treatment.[5] Social inequality in cancer rehabilitation - The University Hospital in Copenhagen and the Health Care Center in Copenhagen are developing a concept for motivational conversations offered to vulnerable patients. The hospital assesses the need for cancer rehabilitation to those expected to be at risk of saying no to a rehabilitations process. It is a nurse who coordinates the project.[6] Proluca (the value of Postoperative Rehabilitation of Operation for cancer) is a research project in which the effect of early training after surgery for lung cancer is evaluated. The project aims to investigate whether training shortly after surgery for lung cancer can lead to an improved performance in the post-operation phase. It is as a nurse who coordinates the project in the health care center in Copenhagen.[7] Good lung cancer care is related to nurse education. In Denmark the Bachelore’s degree programme in Nursing has a duration of 3 and a half years; you can also get an Advanced Cancer Nurse Education – this requires 1 and a half year of training.[8] Taking care of a lung cancer patient can often be complicated and requires nursing care at a high level. On a global scale, Denmark has a lot to offer lung cancer patients, but there is obviously still room for improvement, since this group of patients faces so many different challenges in their everyday life. And it takes well-educated nurses to meet the complex demands of lung cancer patients. [1] www.lungecancer.dk/ [2] www.kraeftcenter-kbh.dk/ [3] www.cancer.dk/international/ [4] www.lungekraeft.com/ [5] lungecancer.dk/documents/F1BFDA1D-EBFD-409A-A26A-15FF5385F00A.pdf [6] www.kraeftcenter-kbh.dk/projekter/social-ulighed [7] www.kraeftcenter-kbh.dk/projekter/proluca [8] www.dsr.dk/

Abstract:
The onset of an MPE usually indicates a significant reduction in prognosis, with a median life expectancy of 3 to 12 months from onset. MPE associated with breast cancer is usually associated with a better than average prognosis whilst lung cancer has the worst prognosis. Confirmation of malignancy and determination of the cell type may be established by increasingly invasive techniques; pleural aspiration cytology, facilitated by ultrasound guidance if the effusion is small or loculated, pleural biopsy, blind or image guided, thoracoscopy (usually now video-assisted) under local or general anaesthesia. Whilst it is reasonable to start with the least invasive procedure suitable in the circumstances, in patients who are reasonably fit it is important to avoid an escalating cascade of failed procedures, each with the risk of causing pleural adhesions and clot formation, making effective palliation more difficult. There is much to commend early acceptance of an approach which combines the best chance of a tissue diagnosis with the best chance of effective palliation. This decision will be influenced by an assessment of prognosis. Prognosis once an MPE has been confirmed is dependent upon the extent of metastatic disease and associated co-morbidity. In a surgically palliated population in-hospital and 30-day mortality was statistically related to blood albumen levels, being 0% and 0.98% in those with normal albumen levels and 6.8% and 19% in those with hypoalbumenaemia (p=0.001) (1). In a series of 278 patients referred to the Department of Thoracic Surgery at the Royal Brompton Hospital over a 72 month period 195 underwent thoracoscopic talc pleurodesis, 39 had a pleuro-peritoneal shunt inserted, 38 had pleurodesis through an intercostal drain, 29 had pleural biopsy alone and 9 were treated with long-term pleural drainage, a total of 310 surgical procedures. Overall median survival was 211 days post operatively. Survival was not significantly different for tumour type or method of palliation but was related to leucocytosis (p<0.0001), hypoxaemia (p=0.014) and hypoalbumenaemia (p0.0001) (2). The summative effect of these factors is shown in the table below. Table 1

No of factors	n	Median survival (days)	95% CI	p
None	39	702	473-931	.00001
One or two	74	200	111-289
Three	23	42	23-61

How might this information be used to personalise treatment options in patients for whom effective systemic therapy does not exist. Those whose prognosis is judged to be less than 2 months (having all 3 adverse prognostic factors) palliation may be achieved by repeated pleural aspiration. If prognosis is judged to be greater than 2 months, and especially if the patient is in a poor general condition, adequate palliation could be achieved by the insertion of an indwelling pleural catheter under local anaesthesia. In fitter patients with an estimated survival greater than 6 months VATS insufflation of talc or the insertion of a pleuro-peritoneal shunt should be considered. The choice of talc or shunt will be dictated by the adequacy of lung expansion during positive pressure ventilation. In many respects these 2 techniques are complementary but having both of these techniques available at thoracoscopy allows affective long-term palliation to be achieved in 95% of patients (3). However pleuro-peritoneal shunts can be complicated by occlusion within 4 months in 15% of cases but spontaneous pleurodesis has usually been achieved by this time (4). Pleurectomy is rarely indicated in the palliation of MPE. Reference List (1) Pilling JE, Dusmet M, Ladas G, Goldstraw P. Predictors of early mortality and morbidity follwoing surgical palliation of malignant pleural effusion. Journal of Thoracic Oncology 2[8], s430. 2007. (2) Pilling JE, Dusmet ME, Ladas G, Goldstraw P. Prognostic Factors for Survival after Surgical Palliation of malignant Pleural Effusion. J Thorac Oncol 5, 1544-1550. 2010. (3) Petrou M, Kaplan D, Goldstraw P. The management of recurrent malignant pleural effusions: The complementary role of talc pleurodesis and pleuroperitoneal shunting. Cancer 75, 801-805. 1995. (4) Genc O, Petrou M, Ladas G, Goldstraw P. The long-term morbidity of pleuroperitoneal shunts in the management of recurrent malignant effusions. European Journal of Cardio-thoracic Surgery 18, 143-146. 2000.

Abstract:
Dignity has been defined as the “quality or state of being worthy, honored or esteemed”[1]. While dignity-conserving therapy is popularly defined as assisted suicide in the setting of terminal illness, it may also be considered as a larger goal of palliation and achieving a “good death”. Chochinov has defined 8 subthemes in the conservation of dignity at the end of life, including continuity of self, role preservation, maintenance of pride, hopefulness, autonomy/control, generativity/legacy, acceptance and resilience or fighting spirit [1]. Based on how patients and their caregivers define dignity, different interventions may be used to target or support physical and/or psychological distress, a patient’s level of independence, patient perspectives and interactions with others. Dignity Therapy as developed by Chochinov involves a brief therapy session, which may be delivered at the bedside, transcribed and shared with friends and/or family, to support the patient in his or her desire to live in the moment, maintain normalcy as best as possible and to seek spiritual comfort. More commonly, however, dignity conserving therapy refers to physician-assisted death. This has been legalized in at least 8 countries, including the Netherlands, Belgium, Switzerland, Germany, Luxembourg, Columbia, Canada and 6 states in the USA [2]. In Canada, recent legislation decriminalized medically assisted death. Li et al have reported the University Health Network (UHN, Toronto, Canada) experience of establishing a hospital-based physician-assisted program of medical assistance in dying (MAiD) [2]. Three teams were developed including a clinical team, an assessment team and an intervention team. The clinical team is involved in the usual care of the patient, including nurses, allied health professionals, consulting physicians and the physician most responsible for the patient’s care. Upon patient request, the most responsible physician refers the patient to the hospital MAiD program. At this point, full palliative consultation and support is offered if not already in place. An assessment team of two physicians, with expertise in the assessment of prognosis, patient suffering and capacity or ability to provide informed consent, evaluate the patient (MAiD medical specialist, palliative care physician, psychiatrist). To be eligible for MAiD through the UHN program, a person is required to have health care services covered through the Canadian public healthcare system, to be at least 18 years old and capable of making his or her own health care decisions, and to have a grievous and irremediable medical condition. This includes a serious and incurable illness, disease or disability, to be in an advanced state of irreversible decline in capability, such that the illness or state of decline causes enduring physical or psychological suffering that is intolerable to the person and cannot be relieved by means that the person considers acceptable. Natural death must be reasonably foreseeable based on medical circumstances, the request for medical assistance in dying must be voluntary and the person is required to voluntarily provide informed consent after being informed of alternative means to relieve suffering including palliative care. Disagreements between assessors are resolved through discussion involving leaders of the MAiD program. Once deemed eligible for MAiD, the patient completes a request form for the procedures, followed by a mandatory reflection period of at least 10 days unless death or loss of capacity is imminent. The intervention team, comprised of physicians and/or a nurse practitioner, conducts a final evaluation of the person and ensures they retain capacity before obtaining final informed consent and providing the intervention. Psychosocial professionals are available to provide support to family as needed and to conduct debriefing sessions for staff before and after the intervention. A multidisciplinary quality committee provides oversite and reports to the hospital Medical Advisory Committee. Since the program’s inception in March 2016, 111 inquiries have been received, 39% information-seeking only [Dr. Madeline Li, personal communication]. Of these, 71% have a cancer diagnosis, commonly lung cancer. Other diagnoses include neurologic disorders such as ALS (14%), cardio-respiratory chronic disease including CHF, COPD, and interstitial lung disease (9%). Assessments have been conducted for 41 individuals, 7 were found ineligible, 35 have been approved and 24 have completed interventions. Many of these were already receiving specialty palliative care services. The most common reason for not proceeding with the intervention was clinical decline or loss of capacity. Those that received MAiD cited loss of autonomy as the main reason behind their request [2]. Preserving dignity in the face of incurable lung cancer remains a challenge for patients, families and their health care providers. An individualized approach and involving a multidisciplinary support team including palliative care remains key. References: 1. Chochinov HM. Dignity-conserving care – a new model for palliative care. JAMA 2002;282:2253-60. 2. Li M, Watt S, Escaf M, Garedam M, Heesters A, O’Leary G, Rodin G. Medical assistance in dying – implementing a hospital-based program in Canada. New Engl J Med 2017;376:2082-8.

Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.

Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).

Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.

Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.

Background:
Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, and SLK. Ensartinib has demonstrated significant anti-tumor activity in both ALK TKI-naïve and crizotinib-resistant NSCLC patients. We report on data from ALK TKI treatment naïve patients.

Method:
Pts with advanced solid tumors and ECOG PS 0-1 were treated with ensartinib 225 mg qd on a continuous 28-day schedule. In expansion phase, pts were required to have measurable ALK+ NSCLC with tissue confirmed centrally via FISH or IHC. Asymptomatic brain metastases were allowed. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results.

Result:
As of 01Apr2017, 102 pts enrolled. In the ALK TKI naïve cohort, 15 (8 female, 7 male) ALK+ NSCLC pts treated at doses ≥ 200 mg evaluable for response. 4 pts had received prior chemotherapy. Median age 59 (34-80) yrs, 60% had ECOG PS 1. Partial response (PR) achieved in 13 pts (87%). Six pts had ALK detected via plasma NGS. In two patients who did not respond to ensartinib, tissue was positive via FISH and plasma was negative. Seven patients had insufficient plasma for NGS evaluation. Median PFS in the initial 13 evaluable ALK+ pts was 25.6 mos with the longest being 44+ mos. The PFS for all patients is still maturing. In 3 pts with central nervous system (CNS) target lesions and no prior radiation, 1 had a complete response (CR) and 2 had PR for an ORR of 100%. Most common drug-related AEs (>20% of pts) included rash (54%), nausea (34%), pruritus (26%), vomiting (25%), and fatigue (21%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (12 pts).

Conclusion:
Ensartinib was well-tolerated and induced responses in ALK TKI naïve ALK+ NSCLC pts, including pts with CNS lesions. Enrollment is ongoing in the phase 3 study of ensartinib vs. crizotinib in ALK TKI naïve NSCLC patients.

Background:
The incidence of venous thromboembolic events all along the course of the disease in advanced-stage lung adenocarcinomas is approximately 15 %. It is plausible that the different molecular subtypes might influence on the risk of thrombosis. Based on our clinical observation, and supported by limited data from isolated small series, patients bearing ALK rearranged tumors could be at a particularly high-risk of thromboembolic disease.

Method:
We included consecutive patients diagnosed with advanced-stage ALK fusion positive non-small cell lung cancers (NSCLC) between January 2012 and December 2016. Clinical data were contributed by 29 Medical Centers from Spain and one large Academic Cancer Center from Portugal. Investigators at each institution retrospectively reviewed patients’ medical records. A thromboembolic event was defined as any venous or arterial thromboembolism, or both, at any site, documented by appropriate imaging studies, that occurred at the time or after advanced-stage cancer diagnosis.

Result:
A total of 241 ALK-rearranged NSCLCs were included in our study. Half of the patients were never smokers (52 %), and most had stage IV pulmonary adenocarcinomas (n=204, 85%). Baseline brain and liver metastasis were detected in 22 % and 25 % of the patients respectively. Seventy-three patients (30 %) developed thromboembolic disease. In 54 patients (74 %) thromboembolic complications occurred within the first 6 months from diagnosis. In the multivariate competing-risk regression analysis, the presence of baseline liver metastases (HR of 1.85, CI 95 % 1.09-3.15; p = 0.021) and baseline leukocyte counts > 11.0000 cells/mm3 (HR of 2.34, CI 95 % 1.43-3.82; p = 0.001) were independent predictors of thromboembolic disease. Remarkably, 50 % of the patients with either liver metastases or leukocytosis at diagnosis developed thromboembolic disease. Patients experiencing thromboembolic events had shorter median overall survival (OS) (20 months) than patients without thrombosis (36 months) (p = 0.035). In the multivariate Cox Model, thromboembolic disease remained associated with worse OS (HR of 1.70, CI 95 % 1.10-2.62; p = 0.016) when considered as a time-varying covariate. The presence of baseline thromboembolic disease (n = 24) was associated with a numerical non-significant increased risk of death (HR 1.67, CI 95 % 0.96-2.91; p = 0.068).

Conclusion:
Venous and/or arterial thromboembolic complications occur in a high proportion of patients with advanced-stage ALK fusion positive NSCLCs, particularly in the presence of baseline liver metastasis or leukocytosis. The development of thromboembolic disease is associated with a lower OS in these patients.

Background:
Brain metastases are common in patients with advanced non–small cell lung cancer (NSCLC). Approximately 1% of NSCLC patients have ROS1-rearranged, and these patients achieved prolonged survival when treated with crizotinib, which is approved for the treatment of ROS1-rearranged NSCLC. However, this efficacy might not translate to intracranial control of disease. Herein, we evaluated the clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged NSCLC.

Method:
Between April 2014 and October 2016, 53 ROS1-rearranged NSCLC patients treated with crizotinib were retrospectively evaluated for baseline characteristics, brain metastases status, progression patterns and the overall prognosis.

Result:
Of the 53 ROS1-rearranged NSCLC patients who received crizotinib as treatment, 13 (24.5%) patients had baseline brain metastases before crizotinib treatment. Among patients without baseline brain metastases who developed progressive disease after initiation of crizotinib (n=27), 22.2% were diagnosed with brain metastases. Among patients without baseline brain metastases, systemic progression-free survival (PFS) and overall survival (OS) after initiation of crizotinib was significantly longer than that of patients with brain metastases (median PFS: 20.4 months vs. 11.0 months, p = 0.003; median OS: not reached vs. 16.5 months, p = 0.027). There was no significant difference in systemic PFS and OS between patients developing brain metastases before and after crizotinib treatment (median PFS: 11.0 months vs. 6.4 months, p = 0.469; median OS: 16.5 months vs. not reached, p = 0.605). Among the patients with baseline brain metastases, 6 had received prior brain radiotherapy and 7 had received no prior radiotherapy. A total of 2 patients in the treated group had an event of brain metastases progression, as compared with 4 patients in the untreated group (33.3% vs 57.1%, p = 0.592). There was no significant difference in intracranial PFS in the previously brain treated patients versus the untreated patients before crizotinib treatment (median intracranial PFS: 12.5 months vs. 11.0 months, p = 0.790).

Conclusion:
Brain metastases status before crizotinib treatment was significantly associated with both PFS and OS in crizotinib-treated ROS1-rearranged NSCLC patients. Patients with brain metastases received prior radiotherapy have not prolonged survival compared with the patients treated with crizotinib alone.

Abstract not provided

Background:
Treatment of ALK-rearranged Non-Small Cell Lung Cancer (NSCLC) relies on ALK tyrosine kinase inhibitors (TKI). However, efficacy of ALK TKI is limited by the emergence of drug resistance. ALK molecular alterations (amplification or mutation) account for about 40% of mechanisms of resistance to ALK TKI. Even though clinical and fundamental data suggest variability in drug efficacy according to the mechanism of resistance, these mutations are rarely investigated in routine practice. While targeted next-generation sequencing (t-NGS) is increasingly used for detecting molecular abnormalities, the impact of this tool in routine detection of ALK alterations is unknown.

Method:
We performed a retrospective multicentric study aiming at determining the frequency of ALK alterations using t-NGS in metastatic ALK-rearranged NSCLC patients progressing upon ALK TKI. Clinical, pathological, molecular characteristics, and patients outcome were collected.

Result:
We identified 22 patients with metastatic ALK-rearranged NSCLC who underwent a rebiopsy at progression on first ALK TKI, between January 2012 and May 2017. There were 12 females and 10 males, median age was 55, 18 patients (82%) were never smokers. Crizotinib was the first ALK TKI in 21 patients (95%). 15 patients (68%) received a second-generation ALK inhibitor and 3 patients (14%) received a third generation of ALK inhibitor. t-NGS on rebiopsy was performed in 16 patients. 6 ALK mutations (37.5%) were identified, including 3 G1202R, 1 C1156Y, 1 V1180L and 1 L1196M mutations . An ALK amplification (6%) was detected in a rebiopsy (6%) by FISH, with no concomitant ALK mutation. All ALK mutations were detected in solid biopsy, 2 ALK mutation was also detected in liquid biopsy. Median Overall Survival from first ALK TKI was 797 days (IC 95% 460-1135) and tended to be longer in patients with a known mechanism of resistance (1135 days Vs 543 days p=0.2).

Conclusion:
Targeted NGS is feasible in routine practice for detection of mechanisms of resistance to ALK TKI in ALK-rearranged NSCLC patients and may help selecting the best treatment at progression upon ALK TKI.

Background:
Advanced ALK+ non-small cell lung cancers (NSCLCs) are effectively treated with ALK tyrosine kinase inhibitors (TKIs). However, clinical outcomes among patients treated with ALK TKIs vary, and the clinical benefit of TKI therapy is limited due to acquired resistance. To date, emerging data suggest that the specific EML4-ALK variant may impact clinical outcome, but whether variant is associated with mechanisms of TKI resistance is unknown.

Method:
We identified 108 advanced ALK+ NSCLC cases with known ALK fusion variants. Progression-free survival (PFS) on ALK TKIs and resistance mechanisms were retrospectively evaluated according to ALK variant.

Result:
The 108 ALK+ cases consisted of: 42 (39%) EML4-ALK v1 (E13;A20), 8 (7.4%) v2 (E20;A20), 45 (41.7%) v3 (E6;A20), 3 (2.8%) v5 (E2;A20), 4 (3.7%) v5’ (E18;A20), 1 (0.9%) v7 (E14;A20), and 5 (4.6%) non-EML4-ALK variants. Given the small numbers of non-v1/v3 cases, v1 and v3 cases were selected for further analysis. Among the 21 v1 and 25 v3 cases treated with first-line crizotinib, there was no significant difference in PFS (HR = 0.81 [95% CI, 0.42-1.57], p = 0.526). Similarly, there was no difference in PFS on second-generation ALK TKIs among 35 v1 and 35 v3 patients who received ceritinib, alectinib, or brigatinib following first- or later-line crizotinib (HR = 1.32 [95% CI, 0.77-2.26], p = 0.308). Interestingly, among 12 v1 and 17 v3 patients who received the third-generation TKI lorlatinib after failure of a second-generation TKI, v3 was associated with significantly longer PFS than v1 (HR = 0.250 [95% CI, 0.09-0.72], p = 0.006). From our cohort, we identified 11 v3 and 14 v1 post-crizotinib biopsies. No difference was noted in the presence of ALK resistance mutations (27% and 21%, respectively; p = 1.000). In contrast, among 30 v3 and 18 v1 post-second generation TKI biopsies, ALK resistance mutations were more common among v3 vs v1 cases (66% vs 44%, respectively; p = 0.147). Furthermore, the ALK G1202R solvent front mutation occurred more frequently in v3 vs v1 (47% vs 0%, respectively; p = 0.001).

Conclusion:
Our findings suggest that EML4-ALK variants 1 and 3 may not be associated with significantly different PFS outcomes on crizotinib or second-generation ALK TKIs. However, ALK resistance mutations, particularly G1202R, occur more frequently in v3 vs v1 post–second generation TKI. Patients with this variant may therefore derive particular benefit from third-generation, pan-inhibitory ALK TKIs. Larger, prospective studies will be needed to confirm these findings.

Background:
ALK resistance mutations are detected in 30-50% of the patients with ALK-positive non-small cell lung cancer (NSCLC) and resistance to ALK tyrosine kinase inhibitors (TKIs). Preliminary data suggests that TKI-resistant patients benefit from further ALK inhibition based on the specific resistant mutations, but clinical data are limited.

Method:
Patients with ALK-positive NSCLC were identified from our institutional database with IRB approval. Tumor specimens from patients with TKI-resistance were analyzed using next-generation sequencing (NGS). We aimed to study the relationship between specific ALK-resistant mutations, patient characteristics and clinical outcomes.

Result:
Among 82 ALK-positive NSCLC patients, we identified 29 cases with advanced disease, TKI resistance, and specimens available for NGS. Twenty-two specimens from 19 patients were adequate for genomic analyses. Patients received a median of 4 lines of treatment for advanced disease including a median of 2 ALK TKIs, with a median overall survival (OS) of 3.3 years. In 9 of 22 specimens, crizotinib was the only TKI received. Ten specimens (45.5%) showed an ALK resistance mutation: one G1128A, one L1152R, four I1171N/T, two F1174V and two G1202R. ALK-resistance mutations were more common with EML4-ALK variant 3 (4/5) than variant 1 (1/5). Three cases with sequential biopsies showed features of tumor evolution, such as a compound mutation (I1171N + C1156Y) or a mutational change (L1152R to G1128A). One case initially had an EGFR L858R mutation, then acquired an ALK rearrangement, then acquired a G1202R mutation. OS was longer in 8 patients with secondary ALK mutation (5.5y) compared to 11 patients without (1.8 y). Using these learnings from an institutional cohort of ALK resistant patients, we designed and are launching a prospective study to characterize ALK TKI resistance, which uses remote-participation and plasma NGS to enroll patients from across the US. Patients with systemic progression while on a next-generation ALK TKI submit blood to a central lab for analysis and banking. Plasma NGS results are returned to the patient and their provider, and including expected TKI sensitivities for any identified ALK-resistance mutations. Through monitoring outcomes, this study can assess if molecularly-guided therapy for ALK TKI-resistance is feasible and effective.

Conclusion:
ALK resistance mutations arise in a large portion of patients and are associated with longer survival. The SPACEW-ALK study (Study of Plasma next-generation sequencing for remote Assessment, Characterization, Evaluation of patients With ALK drug resistance) uses plasma NGS and remote consent to assess ALK resistance and the feasibility of precision resistance therapy for these patients.

Background:
ALK, ROS1 and TRK kinase inhibitors have achieved tremendous success in the treatment of lung cancer patients with abnormal ALK, ROS1 or NTRK gene. However, the emergence of drug resistance limits their long term clinical applications. An ever increasing number of acquired resistance mutations are being reported from the clinic. In addition to the gatekeeper mutations, the solvent front mutations have been recently recognized as common resistance mutations to many kinase inhibitors. For example, the solvent front ALK G1202R mutant conferred resistance to many clinical ALK inhibitors in lung cancer including crizotinib, ceritinib, alectinib, and brigatinib. The same position mutations ROS1 G2032R, TRKA G595R and TRKC G623R rendered resistance to the ROS1 inhibitor crizotinib in lung cancer, pan-TRK inhibitor entrectinib and larotrectinib in colon cancer, and larotrectinib in infantile fibrosarcoma, respectively.

Method:
A conserved glycine residue at the hinge C-terminal forms a hydrophobic sandwich with the kinase beta 1 sheet. Kinase inhibitors often use an aromatic ring or a flat motif to fit through this narrow glycine sandwich to the solvent. Alterations at the conserved glycine or the nearby residues, commonly referred to as solvent-front mutations, clash with the inhibitor motif and induce clinical resistance. Here, we designed TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current ALK, ROS1, and TRK inhibitors in the clinic to avoid the steric clash inside the sandwich.

Result:
TPX-0005 resides at the center of the highly conserved ATP site without direct contact with the solvent front glycine sandwich. As expected, TPX-0005 potently inhibited WT EML4-ALK and solvent front mutant EML4-ALK G1202R with similar activities in both enzymatic (WT Ki 0.87 nM vs G1202R 0.81 nM) and Ba/F3 cell proliferation assays (WT IC~50~ 21.1 nM vs G1202R 20.5 nM). TPX-0005 showed potent activities against CD74-ROS1 G2032R (IC~50~ 8.4 nM), LMNA-TRKA G595R (IC~50~ 0.4 nM), TEL-TRKB G639R (IC~50~ 1.9 nM) and TEL-TRKC G623R (IC~50~ 0.4 nM) in Ba/F3 cell proliferation assays. In the xenograft tumor model studies, TPX-0005 dramatically caused tumor growth inhibition and tumor regression in the tumors carrying WT and solvent-front mutations of ALK, ROS1 or TRKA fusion genes, respectively.

Conclusion:
Taken together, preclinical results demonstrated that TPX-0005 is a novel ALK/ROS1/TRK inhibitor overcoming the profound solvent front kinase mutations. TPX-0005 will bring new methods for the treatment of resistance patients with solvent front mutations in ALK, ROS1, or TRK fusion genes. A phase 1/2 study of TPX-0005 in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements (TRIDENT-1) is actively pursued (NCT03093116).

Abstract not provided

Background:
Trastuzumab emtansine (T-DM1), an anti-HER2 antibody conjugated with vinca-alkaloid, has been approved for clinical use in HER2-positive breast cancer. HER2-alterations are detected even in non-small-cell lung cancer (NSCLC). We have launched a phase II trial of T-DM1 monotherapy for patients with HER2-positive lung cancer.

Method:
Eligible patients had pathologically diagnosed NSCLC with documented HER2-positivity (immunohistochemistry [IHC] 3+, both IHC 2+ and fluorescence in situ hybridization [FISH] +, or exon 20 insertion mutation) and were previously treated with standard chemotherapy. Thirty patients would receive T-DM1 3.6 mg/kg every 3 weeks. The primary endpoint is the overall response rate (ORR) per RECIST v1.1.

Result:
This study was early terminated due to the limited efficacy, leading that only 16 patients were registered. The demographics of the 15 evaluable patients were as follows: age (median; 67, range: 45-77), sex (male; 47%), performance status (0-1; 80%), histology (non-squamous; 100%), HER2 status (IHC3+; 33%, IHC2+/FISH; 20%, and mutation; 47%) and number of prior chemotherapeutic regimens (median; 4, range: 1-7). Of 15 patients, one, who possessed HER2 mutation achieved a partial response, resulting in ORR of 6.7%. None of the 15 patients experienced treatment-related deaths. Survival data would be presented at the meeting.

Conclusion:
T-DM1 has a limited efficacy for HER2-positive NSCLCs in our cohort. Additional molecular approaches are warranted for the precision medicine in HER2-positive tumors. UMIN registration number 000019446.

Background:
There are currently no effective targeted therapies for HER2 mutant lung cancer. Both neratinib alone or in combination with temsirolimus both have low response rates. One challenge is the lack of patient derived HER2 mutant cell line models and a platform in which to identify the most effective therapeutic strategy. Patient derived xenografts (PDXs) are emerging as an alternative tool to screen for drug efficacy, but can take months to generate and are impractical for screening of large sets of drug combinations. Here we report on a novel 3D microfluidic platform that allows for evaluating ex vivo responses to targeted therapies or targeted therapy combinations from patient derived tumor spheroids (xDOTS).

Method:
We generated xDOTS from DFCI 359, a PDX derived from a HER2 mutant (InsYVMA) NSCLC patient under an IRB approved protocol. Tumor organoids (<100 μm and >40μm) were treated with: HER2 covalent inhibitors (neratinib, afatinib); an EGFR inhibitor (gefitinib), and combinations of HER2 inhibitors and other compounds (neratinib/trastuzumab or neratinib/temsirolimus) at known peak plasma concentrations for 3 days in our 3D microfluidic cell culture device. Live/death quantification was performed by dual labeling de-convolution fluorescence microscopy using acridine orange for live and propidium iodide for dead cells. Cell type characterization was performed by immunofluorescence. The most effective combination was used to treat the DFCI 359 PDX and a HER2 InsYVMA genetically engineered mouse model (GEMM).

Result:
Both neratinib alone and afatinib alone, but not gefitinib, induced high degree of cell death in the DFCI 359 xDOTS. The combinations of neratinib/trastuzumab, and neratinib/temsirolimus enhanced the therapeutic benefit compared to neratinib alone, with the former combination being more effective than the latter. Using fluorescence microscopy we demonstrate that the effects are specific to the tumor cells, rather than the stromal component. We then went on to confirm these findings in a concomitant in-vivo efficacy experiment using the DFCI 359 PDX and the HER2 InsYVMA GEMM. In both in vivo models, the neratinib/trastuzumab combination led to significant tumor regressions and was superior to either single agents or the neratinib/temsirolimus combination.

Conclusion:
Our findings demonstrate the ability to use a 3-D in vivo microfluidic system to identify combination therapies for HER2 mutant NSCLC. Based on our studies, neratinib/trastuzumab is a promising combination for a clinical trial for HER2 mutant lung cancer.

Background:
Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.

Method:
We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).

Result:
We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.

Conclusion:
HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.

Abstract not provided

Abstract not provided

Background:
Analysis of circulating tumor DNA (ctDNA) represents a potential strategy for the early detection of lung cancer. Despite significant interest, few studies have evaluated ctDNA levels in early stage lung cancer patients and the feasibility of ctDNA-based screening remains unclear.

Method:
We applied lung cancer-focused Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) to assess ctDNA levels in 55 localized lung cancer patients treated with curative intent (stage I: n=22, stage II: n=7, stage III: n=26) and 50 healthy controls. Histological subtypes included: adenocarcinoma (n=30), squamous cell carcinoma (n=19), NSCLC NOS (n=4), and small cell lung cancer (n=2). Sensitivity and specificity of ctDNA detection were evaluated in all patients and in a subset of NSCLC patients with node negative (N0) stage I-II disease. Additionally, for patients with stage I adenocarcinoma in whom ctDNA was not detectable using the standard population-based CAPP-Seq approach, we designed personalized CAPP-Seq assays covering a median of 320 mutations/patient based on tumor exome sequencing from the respective patients.

Result:
We detected ctDNA in the pre-treatment plasma of 43/55 (78%) patients at a median allele fraction (AF) of 0.48% (range: 0.004%-26.1%). ROC analysis revealed an area under curve of 0.91, with sensitivity and specificity of 78% and 98%, respectively. Among patients with non-adenocarcinoma histologies, 92% (23/25) had detectable ctDNA (median AF: 0.90%), compared to 67% of patients with adenocarcinoma (20/30; median AF: 0.23%; P=0.046). However, tumor volumes were significantly smaller in adenocarcinomas (P=0.01) and in multivariate analysis ctDNA detection was significantly associated with tumor volume (P=0.01) but not histological subtype (P=0.16). In N0 stage I-II NSCLC patients (n=22), ctDNA was detected in 64% of patients (7/14 adeno vs 7/8 non-adeno) with a specificity of 98% and median AF of 0.022% (median AF of 0.018% vs 0.030% in adeno vs non-adeno patients, respectively). Using personalized CAPP-Seq assays, we detected ctDNA in 3/4 patients with stage I adenocarcinoma in whom ctDNA was not detected using our standard lung-cancer focused CAPP-Seq assay. In these 3 patients, tumor volumes ranged from 11.6-14.7 mL and the ctDNA AF ranged from 0.0014%-0.003%. Taken together, we detected ctDNA in 17/22 (77%) N0 stage I-II tumors.

Conclusion:
These data suggest tumor volume is a stronger determinant of ctDNA levels than histology in localized lung cancers. Additionally, our findings suggest that the majority of localized lung cancers shed ctDNA and that ultra-sensitive assays will be required for early detection of lung cancer using ctDNA

Background:
Recently, anti PD-1/PD-L1 immunotherapies have yielded promising outcomes in advanced squamous NSCLC. Several studies have suggested that tumor PD-L1 protein expression status might correlate with outcome and response to treatment. The aim of this study is to identify mRNA gene signatures and microRNAs associated with tumor PD-L1 expression in early-stage lung squamous cell carcinoma (SCC).

Method:
Early stage (I-II) SCC resected patient tumors were collected from 6 cancer centers as part of the SPECS II program. Gene expression profiling was performed on the specimens. PD-L1 protein expression was evaluated by immunohistochemistry on SCC FFPE tissue using the Dako 22C3 PD-L1 antibody. The tumor proportion score (TPS) for PD-L1 protein expression was compared with comprehensive clinicopathological, mRNA and miRNA data.

Result:
The prevalence of PD-L1 expression in this cohort of 255 Stage I-II SCC patients was 46.7% with a TPS cutoff of ≥ 1%, and 9.8% with a cutoff of ≥ 50%. Among 202 cases with available clinical and expression data, no significant association was observed between PD-L1 expression and clinical outcome. We identified a 12-gene signature from mRNA microarray using the Minimax Concave Penalty (MCP) regression method with an AUC of 0.92 at ≥ 5% TPS cutoff. A subset of 138 miRNAs was shown to be significantly differentially expressed between PD-L1 positive and PD-L1 negative groups at false discovery rate (FDR) of 0.05 with TPS cutoffs of ≥ 1%, ≥ 5% and ≥ 10%. No miRNAs were found to be significantly differentially expressed between the groups using a TPS cutoff of ≥ 50%. Gene Set Enrichment Analysis (GSEA) identified two pathways with gene sets that were significantly enriched (FDR < 0.05) in the PD-L1 negative group. No significant association was found between tumor mutation burden and PD-L1 expression level.

Conclusion:
PD-L1 expression prevalence is lower in early-stage lung SCC than in advanced NSCLC. No significant association was found between PD-L1 expression and prognosis in this cohort. Both mRNA gene signatures and miRNAs were identified to be predictive of PD-L1 expression. Through GSEA, two distinct gene sets were identified with expression correlated to PD-L1, one comprising genes related to ovary and another related to collagens and extracellular matrix (ECM). No significant association was found between tumor mutation burden and PD-L1 expression level. Following validation, these predictive signatures could be used to select patients with positive PD-L1 expression who may benefit from immunotherapy.

Background:
Adjuvant chemotherapy (ACT) for ES-NSCLC has a modest improvement in survival but it is often associated with serious adverse effects. Thus, identifying subgroups of ES-NSCLC patients who may benefit from ACT is of high clinical relevance. We evaluated the prognostic and predictive role of quantitative spatial profiling of PD-1/PD-L1 interaction in the tumor cells of ES-NSCLC patients.

Method:
451 whole tissue sections of formalin-fixed, paraffin embedded surgical resection specimens from ES-NSCLC patients with/without ACT were tested with a multiplexed fluorescence immunohistochemistry assay to detect PD-1, PD-L1, cytokeratin and DAPI labeling. Fluorescence Images were acquired on the Perkin Elmer Vectra platform and analyzed with AQUA® algorithms to determine the percent positivity of each biomarker as well as the co-localization of PD-1 and PD-L1 (the Interaction Score).

Result:
High PD-1/PD-L1 Interaction Scores correlated with improved progression-free and overall survival for ES-NSCLC patients receiving ACT after surgery (p = 0.01) whereas no difference in survival was observed for patients who received surgery alone (p = 0.9) (Figure 1). Interestingly, the levels of PD-1 or PD-L1 alone did not demonstrate any difference in survival for surgery + ACT or surgery alone patient populations. Figure 1



Conclusion:
PD-1/PD-L1 Interaction Score is predictive of benefit from ACT in patients with ES-NSCLC. Future studies will determine if this tool can be used to select patients that may be spared chemotherapy without compromising outcome.

Background:
Stereotactic body radiation therapy (SBRT) is currently the standard of care for inoperable patients with early stage non-small cell lung cancer (NSCLC). Despite this, ≈20% will relapse at 2 years. While adjuvant chemotherapy is recommended for surgically resected patients with early stage NSCLC (IB-IIIA), data on the role of adjuvant systemic therapy following SBRT for early stage NSCLC are sparse. The goal of this study was to evaluate the role of adjuvant chemotherapy following SBRT in early-stage, inoperable NSCLC.

Method:
Adults diagnosed with early-stage (clinical stage I and II) between the years of 2004 and 2013 were identified from the National Cancer Database (NCDB). Variables abstracted included: age, gender, clinical stage, race, comorbidity, insurance status, treating facility, treatment received and survival. Chi-square tests were used to compare clinical characteristics by therapy type. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses.

Result:
Data from 12,414 patients with early-stage NSCLC were analyzed. Of these, 75.6% and 25.4% had clinical stage I and II disease, respectively. A total of 9,164 (73.6%) patients received SBRT alone and 3,268 (26.4%) had SBRT followed by chemotherapy. Among patients with clinical stage I, 83.5% received SBRT alone and 16.5% received SBRT followed by chemotherapy. Among those with clinical stage II, 43% received SBRT alone while 57% received SBRT followed by systemic therapy. On multivariate analysis, increasing age, male gender and stage II disease were associated with worse overall survival (OS). There was evidence of a clinical stage by treatment interaction (p <0.001). When treatment effect was analyzed by stage after adjusting for age and gender, patients with stage I treated with SBRT alone had a better median OS, 26.2 months compared to 22.4 months in the combined arm (HR=0.78; p<0.001; CI: 0.73-0.83). In contrast, among patients with stage II NSCLC, median OS was 15 months in the SBRT compared to 20.2 months in the combined group (HR=1.3; p<0.001; CI: 1.22-1.44).

Conclusion:
SBRT should be the sole modality treatment for patients with inoperable stage I NSCLC. However, patients with stage II disease appear to benefit from adjuvant chemotherapy. Randomized trials are needed in this area to answer this question conclusively.

Abstract not provided

Background:
Stereotactic body radiation therapy (SBRT) provides over 90% local tumor control, is a treatment of choice in patients with early stage medically inoperable non-small cell lung cancer (NSCLC). However, long-term overall survival after SBRT remain suboptimal, with 5-year rates rendering less than 50%, which cannot be fully explained by comorbidity, distant tumor progression or commonly known toxicities. We hypothesize that doses of radiation to normal lung and heart contribute to poor survival in these patients.

Method:
Patients with T1-T2 NSCLC received more than 100 Gy BED and with retrievable RT plan were eligible. The primary endpoint was overall survival, calculated from the start of SBRT. Clinical factors included age, gender, race, tobacco history, respiratory and cardiovascular comorbidity, tumor lobar location, histology, T stage, gross tumor volume (GTV), planning target volume (PTV), and prescription dose. Heart and lung were contoured consistently by one radiation oncologist according to the RTOG atlas. Dosimetric factors of the total lung were computed with biocorrection of fractionation effect.

Result:
A total of 280 patients with T1-3N0 met criteria. The median follow-up were 47 months. The median survival time was 33 months (95% CI: 25-42 months). The 2-year, 3-year and 5-year survival rates were 63%, 53% and 45%, respectively. Univariate analysis demonstrated that age (HR=1.02, p=0.04), gender (HR=0.75 for female, p=0.07), tumor T stage (HR=1.3 for T2, 2.5 for T3, using T1 as the reference, p=0.10), GTV (HR=1.01, p<0.001), PTV (HR=1.01, p<0.001), mean lung dose (HR=1.2, p<0.001), V5 (HR=1.02, p=0.03), V10 (HR=1.03, p=0.01), V20 (HR=1.1, p<0.001) of total lung and mean heart dose (HR=1.001, p=0.029) were associated with survival probability. The median mean lung and heart doses were 4.1Gy (range 0.8-11.2) and 0.99 Gy (range 0.3-9.7), respectively. Presence of radiation pneumonitis was not significant (p>0.1). Multivariate analysis was not performed as the dosimetric factors were correlated with each other. Among the risk factors, lung dosimetric factors were most significant. Increase in dose or volume of lung was significantly associated with poorer overall survival. A 1 Gy increase in mean lung dose corresponded to a 12 % increase in the risk of death, or 5% reduction in 5-year survival.

Conclusion:
This study demonstrated at the first time that doses to lung and heart are significant for overall survival after SBRT, while radiation pneumonitis was not. This suggests that the suboptimal survival after SBRT may be improved with plan optimization. This data also challenges the current practice of toxicity based normal tissue dose tolerance policy.

Background:
NRG Oncology RTOG 0915/NCCTG N0927 was a randomized lung stereotactic body radiotherapy (SBRT) trial of 34 Gy in 1 fraction (arm 1) versus 48 Gy in 4 fractions (arm 2) designed to select the better of the 2 regimens by comparing them at 1 year (yr): first by rates of pre-specified protocol-specified adverse events (psAEs), then by primary tumor control for each arm. 34 Gy emerged as the least toxic yet equally efficacious regimen. Herein, we update those results with long-term follow-up.

Method:
This phase II North American multicenter study of patients aged 18 yrs or older with medically inoperable non-small cell lung cancer with biopsy-proven peripheral (≥2 cm from the central bronchial tree) T1 or T2, N0 (clinically node negative by positron emission tomography), M0 tumors was designed to detect 1-yr psAEs rates >17% as primary endpoint. Primary tumor failure (PTF) (either infield or marginal failure) and local failure (either infield, marginal, or involved lobe failure) [with death without failure considered as a competing event]; overall survival (OS); disease-free survival (DFS) and progression-free survival (PFS) were secondary endpoints, but the study was not designed for statistical comparisons of these outcomes. The study opened in September 2009 and closed in March 2011. Updated data were analyzed through November 14, 2016.

Result:
Ninety four patients were accrued, with 86 eligible for analysis: 41 in arm 1 and 45 in arm 2, after 8 cases were excluded. Median follow-up time was 3.8 yrs for all patients, and 5.1 yrs for those alive at analysis. The grade 3 and higher treatment-related toxicity profile was unchanged since previous report, with specifically no new high grade chest wall or grade 5 events. Four of 48 Gy patients had subsequent grade 3 changes in spirometry since meeting the primary endpoint. Medians (in yrs) for 34 Gy and 48 Gy were: 4.1 vs. 4.0 for OS, and 2.6 vs. 2.8 for DFS, respectively. Five-yr outcomes as % (95% CI) for 34 Gy and 48 Gy were: PTF rate of 7.9 (2.0, 19.5) vs. 6.8 (1.7, 16.9); OS of 28.8 (15.4, 43.8) vs. 40.2 (24.9, 55.0); PFS of 19.1 (8.5, 33.0) vs. 31.8 (18.6, 45.9); and second primary rate of 15.5 (6.1, 28.9) vs. 13.3 (5.3, 25.1), respectively. Distant failure as the sole failure or a component of first failure was numerically higher in the 34 Gy arm (7 (46.7%)), but in the 48 Gy arm, rate of second primary development was higher (7 (43.8%)). Approximately 1/3 of patients’ causes of death was unknown, and another 1/3 was related to causes other than cancer or treatment.

Conclusion:
No excess in late-appearing toxicity was seen in either arm. Primary tumor control rates at 5 yrs were similar by arm. Median survival times of 4 yrs for each arm suggest similar efficacy pending any larger studies appropriately powered to detect survival differences.

Background:
There is a paucity of data on the long-term outcomes following lung SBRT. This impacts our understanding of late toxicity, relapse patterns and rates of second lung cancers. We report our multi-institutional outcomes of those who survived ≥5 years from lung SBRT treatment.

Method:
1192 patients were treated for primary non-small cell lung cancer, T1/2N0 from 5 international institutions. For those who survived ≥5 years from lung SBRT treatment details of patient factors, treatment and outcome factors were extracted from the multi-institutional database. All events were calculated from the end of radiotherapy. Local (LR), regional (RR), and distant metastases (DM) and toxicity events after 5 years are reported. New cases of metachronous lung cancers after 5 years are reported. Univariable analyses was performed to determine factors associated with survival ≥5 years.

Result:
Of 1192 patients there were 182 (14%) ≥5 year survivors. Only 52 (8%) survived ≥ 7 years and 2 (0.2%) ≥10 years. Those surviving ≥5 years were younger (74.3 vs 71.5 years; p<0.01) and had better FEV1 (55% vs 65%; p<0.01) than those that did not survive 5 years. The Charleston Comorbidity Score was 1.4 (0-12) vs 2.1 (0-7) (p<0.001) in those who survived < vs ≥5 years. Those who survived <5 years had a trend to larger tumors (2.4cm vs 2.3 cm; p=0.07). Of the 182 patients 23 (13%) were operable, 67 (37%) were <70 years old at treatment, 115 (63%) were ECOG 0-1 and 156 (86%) had peripheral tumor location at time of initial diagnosis. 84 (46.2%) were T1a, 60 (33%) T1b, 33 (18.1%) T2a and 5 (2.7%) T2b. After 5 years there were 13 new events of grade ≥ 2 toxicity. These toxicities were 4 grade 2 fatigue, 1 grade 2 rib fracture, 7 grade 2 chronic myositis and 1 patient with grade 2 chronic myositis and fatigue. In this 182 patient cohort, after 5 years, there were 3 local recurrences, 2 regional failures and 5 distant failures. After 5 years follow-up there were 22 (12%) new primary lung tumors in the 182 patients (and 20 had a subsequent lung SBRT treatment).

Conclusion:
Late survivors after SBRT require dedicated follow-up as they remain at risk for second lung cancer, tumor recurrence and toxicity. Second cancers in these late survivors can be considered for SBRT treatments.

Abstract not provided

Background:
The regularity of intrapulmonary lobar and segmental lymph node (LSN) metastasis in cT1N0M0 stage lung adenocarcinoma remains unclear. Thus, segmentectomy with uncertain LSNs metastatic status remains a potential oncological risk. We aimed to facilitate more accurate determination of N staging and identification of more suitable cases for segmentectomy.

Method:
A prospective study was performed from March 2014 to March 2016. A total of 156 patients diagnosed with cT1N0M0 stage lung adenocarcinoma received lobectomy and mediastinal lymph node dissection. The intrapulmonary LSNs were dissected and classified as adjacent LSNs or isolated LSNs. The metastatic status of the LSNs together with the TNM stage were analyzed. A comparison of the metastatic probability of isolated LSNs was carried out considering imaging features, serum carcinoembryonic (CEA) levels, pathological subtypes, size of the lesions, and metastatic status of adjacent LSNs.

Result:
Among the 156 cases enrolled, 129 were confirmed as pN0, 21 as pN1, 5 as pN1+N2, and 1 as skip pN2. When the LSNs had not been dissected, the false negative rate for N staging was 5.1% (7/136). Patients with a pure ground-glass-nodule had a lower isolated LSN metastasis rate (p = 0.027). Non-lepidic predominant invasive adenocarcinoma (p = 0.003), the cT1c group (p = 0.020), and those with adjacent LSN metastasis (p < 0.001) were detected with a higher isolated LSN metastasis rate. No significant difference in isolated LSN metastasis rate was found between groups with different serum CEA levels (p = 0.121).

Conclusion:
Dissection of intrapulmonary LSNs reduces the false negative rate of lymph node metastasis. Partial solid or solid lung adenocarcinoma, non-lepidic predominant invasive adenocarcinoma, and cT1c lung adenocarcinoma might not be suitable for segmentectomy. The lymph node sampling area during segmentectomy should include adjacent LSNs of the target segment. When metastasis to the adjacent LSNs is confirmed by fast frozen pathology, segmentectomy would not be suitable.

Background:
Sublobar resection is widespread for selected patients with small sized non-small cell lung cancer (NSCLC). Segmentectomy has been considered superior to wedge resection, however well-balanced comparative studies are lacking. We compared oncologic outcomes between wedge resection and segmentectomy for patients with less than 2cm of NSCLC according to parenchymal safety margin

Method:
A retrospective review of a prospective database was performed (2003-2015), excluding patients with poor lung function (FEV~1~ or DLCO <50%), neoadjuvant therapy, previous lobar resection for primary lung cancer, and multiple primary other cancer. Demographic, clinical, and pathological data were reviewed. Overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method and differences compared using log-rank test. Lymph nodes (LN) were evaluated preoperatively by PET/CT and EBUS-FNA if chest CT showed more than 1cm of LN short diameter

Result:
Two hundred nighty-six patients met our selection criteria, including wedge resection (W) in 188 and segmentectomy (S) in 108. There was no difference in smoking history, comorbidity, pulmonary reserve, cell type, and postoperative complication rate. All enrolled patients had clinically negative LN and 3 patients (1 in W, 2 in S) had pathologically node positive LN. The segmentectomy had more likely to have larger tumor (1.26 vs 1.36, p=0.045), more total nodes resected (1 vs 6, p<0.001), more distance of safety margin (median 0.5 vs 1.5, p<0.001). There was no statistical difference in OS (p=0.897), CSS (p=0.844), and RFS (p=0.763) between two groups. Patients were stratified by safety margin into ≤ 5mm in 118 (w101 vs s17), 5~10mm in 65 (w48 vs s17), 11~15mm in 45 (w23 vs s22), 16~20mm in 23 (w9 vs s14), and >20mm in 45 (w7 vs s38). Recurrence was developed in 8 (7%, w5 vs s3), 2 (3%, w2 vs s0), 1 (2%, s1), 0 (0%), 1 (2%, s1) of each safety margin. There was no significant difference of RFS between wedge resection and segmentectomy in each safety margin

Conclusion:
Wedge resection and segmentectomy showed comparable oncologic outcomes for carefully staged less than 2cm NSCLC patients. After thorough preoperative LN evaluation, wedge resection of sufficient safety margin is good surgical option

Background:
Spread through air spaces (STAS), defined as “micropapillary clusters, solid nests, or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma” (Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart, 2015), has been recognized as a pattern of tumor invasiveness. Because complete lymph node dissection and sufficient surgical margin lengths are difficult to obtain, wedge resection is associated with worse surgical outcomes than those of lobectomy. Because of the insufficient margin length associated with wedge resection, we speculated that STAS has a prognostic impact in wedge resection cases compared with segmentectomy cases. The aim of this study was to clarify the prognostic impact of STAS in patients with non-small cell lung cancer (NSCLC) who underwent wedge resection.

Method:
This was a retrospective study using our prospectively collected institutional database, established in May 2004. From May 2004 to May 2017, 1071 patients with NSCLC underwent complete resection. After excluding patients with pure ground glass opacity or multiple lung cancers and those who underwent lobectomy or preoperative therapy, we evaluated 196 patients with clinical stage IA cancer who underwent segmentectomy or wedge resection. TNM staging was performed according to the seventh edition. We assessed the prognostic impact of STAS on stage IA lung cancer cases who underwent wedge resection compared with segmentectomy.

Result:
Segmentectomy was performed in 110 patients and wedge resection in 86. The wedge resection cases were older (p<0.001) and had a higher CEA level (p=0.023). The frequencies of STAS were 14.5% and 18.6% in the segmentectomy and wedge resection cases, respectively (p=0.447). STAS was a significant prognostic factor for overall survival in the wedge resection cases on univariate (p=0.003) and multivariate (p=0.013) analyses, but it was not significant in the segmentectomy cases (p=0.597). STAS was a significant prognostic factor for disease-free survival in the wedge resection cases on univariate (p<0.001) and multivariate (p<0.001) analyses, but this was not the case in the segmentectomy cases (p=0.108). STAS was a significant prognostic factor for the recurrence-free rate in the wedge resection cases on univariate (p<0.001) and multivariate (p<0.001) analyses, but it was not significant in the segmentectomy cases (p=0.205).

Conclusion:
STAS is a prognosticator of poor survival outcomes in NSCLC patients who underwent wedge resection, but not in those who underwent segmentectomy. We speculate that NSCLC with STAS tends to have invasive characteristics, and wedge resection is not sufficient to improve survival outcomes in such patients.

Background:
The early detection and improved survival of resected non-small cell lung cancer (NSCLC) may increase the number of patients who eventually undergo subsequent pulmonary resection. We investigated the surgical outcomes and survival of patients following second and third pulmonary resections for NSCLC.

Method:
Patients who underwent second or third pulmonary resections without induction therapy for synchronous or metachronous NSCLC (511 patients, 535 procedures, 2000-2014) were included in the analysis.

Result:
Among 535 operations, 361 (67%) were sublobar resection and 103 (19%) were performed by minimally invasive approach, with the proportion of minimally-invasive procedures increasing in recent years (Fig. 1). The majority of re-resections were performed within 4 years of the previous resection (Fig. 2). Risk regression analysis demonstrated that predicted postoperative (ppo) FEV1 (p<0.001) and same side operation (p=0.002) were independent risk factors for severe complications (CTCAE grade ≧ 3; N=45). Multivariable Cox regression analysis revealed that age at subsequent surgery, male sex, ppoDLCO, interval from prior surgery, and tumor stage were independently associated with overall survival.

Conclusion:
In this large cohort of pulmonary re-resections for NSCLC, predicted postoperative pulmonary function tests were indictive of major complications and overall survival. Figure 1 Figure 2

Abstract not provided

Background:
The objective of the study was to compare the program of early detection of lung cancer by low-dose computed tomography scan with other groups of lung cancer patients who live in the area where such a program is carried out. The study was based on the materials of one thoracic surgery clinic and the screening was carried out on the inhabitants of one district city. The objective of the study was implemented by analyzing selected factors that impact the activities of surgery ward. The study was retrospective.

Method:
The patients were divided into three groups. Group 1a - 52 patients operated due to primary lung cancer which were detected during the screening. Group 1b - 87 patients operated for primary lung cancer during the screening, but who did not participate in the screening program. Group 2 - 103 patients operated before the commencement of the screening. The analysis involved among others the factors described in the table below. For the statistics we utilised Statistica PL 2010 program. Non parametric Mann-Whitney U-test was used for not normally distributed data. Parametric t-Student test was used for normally distributed data and p<0.05 was considered significant.

Result:

Significant differences among the groups

		Group	Group	Group	Statistics	Statistics
	unit	1a	1b	2	p 1a/1b	p 1a/2
Patiens	n	52	87	103	-	-
Adenocarcinoma	%	58	34	38	0.01	0.03
G2 grading	%	44	28	24	0.03	0.02
Tumour volume	cm[3]	8	21	20	0.004	0.01
T1 factor	%	54	28	34	0.004	0.02
IA stage	%	50	24	32	0.003	0.02
Right side	%	73	63	59	ns	0.05
Lobectomy	%	75	53	56	0.02	0.04
Operation time	min	129	114	112	0.02	0.007

Conclusion:
In the screening 1a group adenocarcinoma was detected more frequently, as a smaller tumour, at an earlier stage, with the prevalent G2 factor and located mainly on the right side. In the group 1a lobectomy was performed more frequently, than the other groups. The duration of surgery of 1a group was longer than the other groups due to more often intraoperative assessment use. There were no differences according to postoperative complications and deaths among all groups. Our screening program detectes lung cancer at earlier stage and offers faster definitive surgical treatment, probably improving 5 year survival, what is being evaluated now.

Background:
Imaging screening programs are designed for specific eligibility criteria and technologies. Effectiveness of these programs is precisely known only after monitoring large populations over a long period. Ensuring generalizability of screening programs is required when targeting a population which is different from the original one tested or when modifying involved technologies. The NELSON screening program is a lung cancer triage process featuring four rounds of variable intervals (1, 2 and 2.5 years). Each screening round classifies the nodule’s malignancy according to the nodule’s volume, growth and volume doubling time, using CT. The aim of our study was to assess by simulation the influence of variable precision of measurement on the robustness of NELSON’s diagnostic algorithm.

Method:
We simulated 10[6] nodules using a Chi[2] distribution for nodule size [3mm; 20mm], an inverse Chi[ 2] distribution of growing. 2.1% of nodules were malignant (true positive). We tested several distributions of measurement error using a zero-mean Gaussian distribution and a standard deviation (SD) ranging [0%; 20%]. We reported positive and negative predictive values (PPV, NPV) at each round.

Result:
After round 4, we found that NPV decreased with increasing measurement error from 100% to 99.89%, PPV decreased from 100% to 29.6%. Figure 1 Figure 1: Detection performances of NELSON’s triage algorithm depending on measurement error. As shown in this graph, an increase of SD leads to a decrease of PPV (gray curve) and has almost no impact on NPV (yellow curve).



Conclusion:
Increasing measurement error of nodules significantly degrades the positive predictive value of NELSON’s diagnostic algorithm in identifying malignant pulmonary nodules, whereas the negative predictive value remained stable. We confirmed the efficacy of the successive rounds when measurement error is larger than 5%; however, the algorithm could be improved for larger measurement errors. Simulations could help us to assess better strategies lung in screening studies.

Background:
There is a need for more accurate and minimally invasive methods to screen high risk populations and diagnose lung cancer during its asymptomatic early stages. microRNAs (miRNAs) are small, non-coding strands of RNA that are shown to lead to carcinogenesis when dysregulated. miRNAs, expressed in a tissue specific manner, are stable and detectable in small quantities, thus are promising candidates for biomarkers. Through the use of previous miRNA profiling done in our group, we aim to validate this panel in a large sample size of non-small cell lung cancers (NSCLC) using miRNAs 21, 155, 210, and 223 in blood plasma to determine if this miRNA panel is able to differentiate lung cancer cases from controls.

Method:
A nested case-control study of 64 patients with stage I/II NSCLC and 110 healthy controls with similar age, gender, and smoking history was performed. Plasma was provided by Conservant Bio, Lung Cancer Biospecimen Resource Network, and Alberta’s Tomorrow Project. miRNA was isolated using the Qiagen miRNeasy serum/plasma kit. miR-21, 155, 210, and 223 were quantified via RT-PCR using C. elegans miR-39 as a spiked-in endogenous control. Binary logistic regression (SPSS version 15) was performed to develop a combined risk score of the patients’ risk of having lung cancer. Receiver operating curve (ROC) analysis was used to determine risk category cut-off values based on the sensitivity and specificity. Plasma samples were taken 4-7 months post resection and also analyzed and compared to pre-operative samples and controls.

Result:
The cases and controls showed similar age ranges (mean=61.97, SD=7.76; mean=61.38, SD=7.95) respectively. Smoking history was higher in the cases (mean=51.5, SD=29.46) than controls (mean=30.98, SD=10.84). The combined score was dichotomized at -0.4169 into high and low risk categories (sensitivity=81%, specificity=41%, AUC=72.3%), the cases pre-operative samples compared to healthy controls was significantly different (odds ratio=3, p-value=0.003, 95% C.I.=[1.440,6.249]). For the cases post-operative samples compared to healthy controls, the combined score was dichotomized at -0.3255 (sensitivity=77%, specificity=41%, AUC=67%), also showing a significant difference (odds ratio=2.3, p-value=0.023, 95% C.I.=[1.120,4.621]). There is no significant difference in the combined risk score when comparing the pre-operative and post-operative NSCLC samples.

Conclusion:
Through binary logistic regression miRNA profiling has the potential to assist in screening the high-risk population for lung cancer. Used in conjunction with radiologic screening, this approach could allow early detection and treatment of disease while sparing patients unnecessary investigations and biopsies.

Background:
Apatinib is a novel small molecular drug targeting vascular endothelial growth factor receptor-2 (VEGFR-2), which is currently being studied in multiple tumor types. The purpose of this study was to assess the treatment response in non-small cell lung cancer (NSCLC) patients enrolled in a clinical trial of apatinib according to the response evaluation criteria in solid tumors (RECIST) using non-contrast-enhanced computed tomography (CT) texture-based radiomics approach.

Method:
A total of 19 NSCLC patients from our single center participated in the currently undergoing multi-center phase III ANSWER study of apatinib (NCT 02332512). Patients were categorized as responders (CR and PR) and non-responders (SD and PD) according to RECIST criteria. Radiomic texture features were extracted from target lesions in post-therapy CT of NSCLC. Lasso regression was used to establish a model to discriminate between responders and non-responders. The performance of the model was assessed with ROC in both internal and independent validation cohorts.

Result:
Altogether, 108 CT scans were performed. Among them, 75 scans were randomly selected as internal validation group (70%), while the remaining 33 scans (30%) were identified as an independent validation group. Three hundred and eighty-four CT texture parameters were extracted and 21 out of 384 CT texture were finally selected for the model. The area under the curve (AUC) of ROC was 0.903 in the internal validation group, and that of the independent validation group was 0.714. Figure 1



Conclusion:
A radiomic discriminate model was built based on post-therapy CT texture features, which demonstrated a good performance in assessing the therapeutic response in NSCLC patients treated with apatinib.

Abstract not provided

Background:
In 1998, low-dose CT screening for lung cancer was introduced in Hitachi City, Japan. Based on time trend analysis, a significant reduction in lung cancer mortality was observed 4–8 years after introduction of CT screening.

Method:
To evaluate the effectiveness of lung cancer screening, we conducted a cohort study for CT screening participants and X-ray screening participants among Hitachi residents. Citizens aged 50 to 75 who underwent CT screening from 1998-2006 were defined as the CT group, and those who underwent X-ray screening during the same period, but did not receive CT screening throughout the follow-up period were defined as the X-ray group. We investigated lung cancer mortality and all-cause mortality of both groups from the first lung cancer screening of the subject to the end of 2012 using residence registry, the regional cancer registry, and national death statistics.

Result:
From the CT group (17,935 cases, 9,790 men and 8,145 women), 273 cases of lung cancer (1.5%), 72 cases of lung cancer death (0.4%), and 885 cases of all-cause mortality (4.9%) were observed. On the other hand, 164 cases (1.1%) of lung cancer, 80 cases (0.5%) of lung cancer death, and 1,188 cases (7.6%) of all-cause mortality were observed in the X-ray group (15,548 cases, 6,526 men and 9,022 women). The hazard ratios of the CT group to the X-ray group adjusted for sex, age, and smoking history were 0.49 for lung cancer mortality and 0.57 for all-cause mortality.

Conclusion:
Low dose CT screening participants exhibited a 51% reduction in lung cancer mortality during the observation period compared with the X-ray group. Although all-cause mortality also decreased by 43% in the CT group, the decrease in proportion of lung cancer deaths was greater.

Background:
The purpose of the present study was to investigate whether low-dose computed tomography (LDCT) screening is capable of enhancing the detection rate of early-stage lung cancer and reducing lung cancer mortality rate in China, thus determining the appropriate duration of screening and identifying additional risk factors for lung cancers in Chinese population.

Method:
A randomized lung cancer screening study was performed with participants aged 45 to 70 years old who had at least one high-risk factor as follows: 1) a history of cigarette smoking ≥20 pack-years; former smokers who had quit within the past 15 years; 2) cancer history in immediate family members; 3) personal cancer history; 4) professional exposure to carcinogens (asbestos, dust or radiation); 5) long history of passive smoking; or 6) long-term exposure to cooking oil fumes. Participants were randomly assigned to a screening group with alternating years of LDCT screening (R1, R2) or a control group with biennial questionnaire inquiries.

Result:
A total of 6657 eligible participants were enrolled, 3145 participants were assigned to the control group and 3512 were assigned to the baseline LDCT screening (R1) group. 1516 participants (43.2%) underwent the second round of LDCT screening (R2) in the alternate year. At R1 and R2 rounds, 19.6% and 24.0% participants showed non-calcified nodules ≥4 mm on LDCT images. Among these, lung cancer was diagnosed in 44 participants (1.3%) at R1, 12 (0.8%) at R2, and 10 (0.3%) in the control group through either biopsy or cytologic analysis. The proportions of early-stage (0 to I) lung cancer were 97.7% at R1, 91.7% at R2 and 20% in the control group, respectively. At R1, the sensitivity of LDCT for lung cancer screening was 97.7%, the specificity was 76.8%, the positive predictive value was 5.1%, and the negative predictive value (NPV) was 99.9%; at R2, both the sensitivity and the negative predictive value increased to 100%. Two cases of lung cancer-specific deaths occurred in the control group, but no death occurred in the LDCT group.

Conclusion:
Compared to usual care, the two biennial screenings with LDCT led to a 77.7% increase at R1 and 71.7% at R2 in detecting early-stage lung cancer and a 20% decrease in lung cancer mortality. Biennial screening may be at least as efficient as annual screening in terms of detecting rate, sensitivity and NPV. This study provides insights about the non-smoking related risk factors of lung cancer in the Chinese population.

Background:
Advances in cancer screening and therapeutics have led to an estimated 15.5 million US cancer survivors. A history of cancer is a known risk factor for lung cancer. Lung cancer screening (LCS) with low-dose CT (LDCT) and smoking cessation in high-risk populations are recommended standard-of-care practices for cancer survivors, yet knowledge and practice of these interventions is low among PCPs. Hematologists and oncologists commonly provide cancer survivorship care, and yet their practices of and attitudes toward LCS are unknown. Based on prior data, we hypothesized that very few providers (<25%) would report performing LDCT screening while most (>75%) would report providing tobacco cessation services in the last year, and that knowledge of LCS guidelines would be associated with LDCT screening.

Method:
We electronically surveyed all Hematology/Oncology providers (n = 104) at a large academic institution in the Mid-South and its affiliated VA from February to May 2017. The survey queried: LCS/tobacco cessation practices (LDCT screening as primary outcome), perceived cancer screening/tobacco cessation effectiveness, knowledge of USPSTF LCS guideline recommendations and CMS coverage, perceived barriers to LDCT screening, and interest in future provider/patient LCS education and reminder tools. Data were summarized using counts, proportions, means, and medians. We used logistic regression to evaluate the association of LCS guideline knowledge (primary predictor) with reported LDCT screening.

Result:
The overall survey response rate was 73%. Few providers (38%) reported performing LDCT screening in the past year, while almost all providers (95%) reported providing tobacco cessation services. In unadjusted analysis, providers who knew at least three LCS guideline components were more likely to perform LDCT screening (OR 5.96, CI 2.03-17.49; P = 0.001). Only 55% of providers knew at least three LCS guideline components. More providers rated Pap-smear (75%), colonoscopy (71%), smoking cessation (68%), and mammography (39%) as very effective at reducing cancer-specific mortality compared to LDCT (24%). Major perceived barriers included: lack of patient awareness (74%) and patient financial cost (51%). More VA providers (37%) rated lack of a multi-disciplinary screening program as a major screening barrier compared to academic providers (7%) (P = 0.002). Majority of providers (≥ 56%) reported interest in future provider/patient LCS education and reminders.

Conclusion:
LDCT screening is currently an uncommon practice among hematology/oncology providers. Future interventions aimed at the provider, patient, and health system levels are needed to ensure standard-of-care LCS practices in the cancer survivor population. Provider level interventions should incorporate education on screening/tobacco cessation effectiveness and screening guideline recommendations.

Background:
Lung cancer screening is only effective at reducing lung cancer deaths when the highest risk individuals are screened and followed. An individual’s risk of lung cancer, and therefore their screening eligibility, has not been shown to correlate with their perceived risk or intention to participate in screening. While previous studies have suggested many at-risk individuals are supportive of screening, no validated risk perception questionnaire has been used to compare perceived risk and worry with screening preference between eligible and ineligible individuals.

Method:
Participants were current or former smokers aged 55 to 80 years old who presented for medical outpatient specialist appointments at three Australian hospitals. The survey included 1) demographics and previous cancer screening participation 2) objective lung cancer risk measured by PLCOm2012 lung cancer risk prediction model 3) perceived lung cancer risk and worry about lung cancer measured by the questionnaire developed by Park et al and validated in sub-set of National Lung Screening Trial (NLST) participants and 4) preference for screening measured by a five point Likert scale. Eligibility for screening was PLCOm2012 risk >1.5%. Ordinal logistic regression identified factors associated with screening preference.

Result:
760 people 55-80 years old participated, of which 306 were ever-smokers. The participation rate was 26.9%. 23 did not complete either sufficient smoking details for PLCOm2012 risk or screening preference leaving 283 responses. Mean±SD age was 66.3±6.5, 60.4% (171/283) were male, median (IQR) PLCOm2012 risk was 1.28% (0.44-3.11) and 45.6% (129/283) were eligible for screening. Overall screening preference was high; 72.1% (204/283) either agreed or strongly agreed to having screening if offered. Objective lung cancer risk (PLCOm2012) was weakly correlated with both perceived lung cancer risk (r=0.28, p<0.0001) and worry (r=0.21, p<0.001). In univariate analysis, worry (OR 1.37, 95% CI [1.18-1.60], p<0.001), perceived risk (OR 1.10, 95% CI[1.04-1.16], p=0.002) and PLCOm2012 risk (OR 1.06, 95% CI[1.01-1.12], p=0.02) were associated with higher screening preference, but not associated with higher screening eligibility (OR 1.50, 95%CI[0.97-2.30], p=0.06). Age, gender, smoking status, family history of lung cancer and previous screening practice were not associated with screening preference. Only worry remained significantly associated with screening preference (adj-OR 1.33, [95%CI 1.10-1.60], p=0.003) with multivariate analysis.

Conclusion:
Worry about lung cancer appears to be a more important driver for screening preference than eligibility status. This presents a unique challenge when trying to engage with eligible individuals while minimizing screening demand from the ineligible majority.

Abstract not provided

Background:
Nodule size is an important parameter to determine malignancy risk. Semi-automated size measurements have the potential to replace manual measurements due to their higher accuracy and reproducibility, and less inter/intra-user variation. However, controversy exists regarding the relative accuracy of 2D diameter versus 3D volumetric measurement to predict malignancy risk. The objective of this study is to compare nodule malignancy prediction models based on 2D mean diameter versus volumetric measurement, both generated by a CAD Software.

Method:
We analyzed baseline LDCT reconstructed using high spatial frequency algorithm from 1746 participants (47% women, 53% men, age: 62.5 ± 5.8 yrs) in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), who had ≥1 non-calcified nodules ≥3mm in diameter. CAD software (CIRRUS Lung Screening, Radboud University Medical Center, Nijmegen, the Netherlands) performed an automatic nodule segmentation, which could be optimised manually, measurement of mean diameter and volume was generated. Malignant or benign nodule status was confirmed by pathology or prolonged follow-up (median follow-up 5.5 years). Logistic regression models predicting cancer were prepared with one including mean diameter and the other including volume. The discrimination, the ability to classify cancer versus benign nodules correctly, was evaluated by the area under the receiver operator characteristic cure (AUC). The calibration - do predicted probabilities match observed probabilities, was assessed using Spiegelhalter’s z-test and graphically by plotting the observed and predicted mean probabilities of cancer by deciles of model risk.

Result:
There were in total 5878 nodules, including 119 cancers in 115 individuals. Both models gave similar predictive performances. AUC was 0.947 (95% CI 0.922-0.964) in the mean diameter model and 0.946 (95% CI 0.921-0.966) in the volumetric model (p=0.83). The calibrations were similar between the two models (figure). Figure 1



Conclusion:
The predictive performances of nodule malignancy prediction models using mean 2D nodule diameter and 3D volumetric data were indistinguishable.

Background:
We tried a radiomics approach to build a random forest classifier for recognition of epidermal growth factor receptor (EGFR) mutation status in Chinese patients with lung adenocarcinomas using quantitative image features extracted from non-enhanced computed tomography (CT) images

Method:
From October 2008 to December 2015, 355 patients diagnosed with lung adenocarcinomas were included in this retrospective study. They all have complete clinical, pathological, and EGFR mutation status information, and their CT images were scanned before any invasive operation. Tumors with ground glass component or diameter smaller than 2 cm were not included. Their pathological phenotypes and EGFR mutation status were gained from surgical resections. Region of tumors on CT images were segmented semi-automatically first then manually modified by experienced clinicians. 440 quantitative image features were extracted from CT images and fall into four groups: first order statistics, shape and size based features, textural features, and wavelet features. Random forest was used to build the classification model which takes all the features into consideration and make an overall probability of mutation based on the vote of decision trees. The random forest classifier was validated using an independent set and its performance was evaluated using area under curve (AUC) values of the receiver operating characteristic

Result:
355 patients diagnosed with lung adenocarcinoma were enrolled in this study (170 male, 185 female; 54 smokers, 301 non-smokers). The patients all received surgery based treatment and their tumor stage varied from I to IV. EGFR mutations (mainly 19del and 21L858R) were found in 187/285(65.6%) and 48/70(68.6%) patients in training and validation sets respectively. The random forest model showed an AUC of 0.781 (95% confidence interval: 0.668-0.894, p<0.001) in the validation set. The sensitivity and specificity are 60.4% and 90.9% at best diagnostic decision point. These results were highest among published results of only using images to detect EGFR.

Conclusion:
The random forest classifier based on CT images showed potential ability to identify EGFR mutations in patients with lung adenocarcinomas and could be improved in future works.

Background:
Previously proposed risk models for the malignancy of Indeterminate Pulmonary Nodules (IPNs) detected on Computed Tomography (CT) typically incorporate a mixture of clinical factors, such as age and smoking history, and radiological factors such as nodule size and location. Of the latter, size is considered one of the most significant. Artificial Intelligence based risk stratification software has been previously proposed that uses Texture Analysis with Machine Learning to predict IPN malignancy and has been shown to achieve high classification performance. While it is assumed that such techniques can capture image texture patterns that separate benignity from malignancy, such methods also intrinsically measure nodule size. The contribution of texture to classifier performance beyond size has not been studied and we seek to quantify this. We show, for the first time, the relative contributions of texture and size on the performance of Artificial Intelligence risk stratification of solid nodules.

Method:
Two datasets were created from the US National Lung Screening Trial (NLST). The first (A), comprising 640 solid nodules, was built to remove size as a discriminatory factor between benign and malignant; all malignant solid nodules between 4 and 20 mm diameter were selected, and for each, a benign solid nodule was selected that most closely matched it in diameter. Any malignant nodule for which an equivalently sized benign could not be found within 0.8 mm was rejected. Sizes were measured using automated volumetric segmentation. The second dataset (B), also comprising 640 subjects, included all malignant nodules in A but benign nodules were randomly selected following the empirical size distribution of the whole NLST dataset. Therefore, nodule size cannot be a discriminative factor in A but would be in B. Two nodule stratification algorithms were developed using Texture Analysis combined with Machine Learning (Support Vector Regression) integrating 20 variables including 3D Haralick, Gabor and Shape features, from A and B respectively using five-fold cross validation and the performance compared measuring Area-Under-the-Curve (AUC).

Result:
The average AUC for the algorithm trained on dataset A was 0.70 whereas using size alone on the same dataset gave an AUC of 0.50. The AUC was 0.91 for the algorithm trained on B.

Conclusion:
On this data, Texture Analysis with Machine Learning contributes 0.20 AUC points to classfication performance. Artificial Intelligence based risk classification can identify radiological features that are predictive of solid nodule malignancy that are independent of nodule size.

Background:
An estimated 330,000 people in the province of Ontario are at high risk of developing lung cancer and eligible for screening with low-dose computed tomography (LDCT). On June 1 2017 Cancer Care Ontario launched the Lung Cancer Screening Pilot for People at High Risk with the purpose of informing the design and implementation of a province-wide organized screening program. Organized screening is available at 3 hospitals, and provider and public recruitment strategies are being implemented to engage the target population in regional catchment areas. Key aspects of pilot design include eligibility based on the PLCO~M2012noRace~ risk prediction model, navigation support, informed participation, embedded smoking cessation services, radiology quality assurance, LDCT findings categorized in accordance with Lung-RADS™, provision of same-visit screening results and seamless transition to a Diagnostic Assessment Program (DAP) for assessment of findings suspicious for lung cancer. Data collected for 3,000 participants over a 2-year period will inform a comprehensive evaluation of the pilot.

Method:
Indicators were selected to assess impacts of early recruitment efforts and outcomes of key screening processes related to eligibility assessment, the LDCT scan and smoking cessation. Data were collected by the pilot sites and submitted to Cancer Care Ontario. Participant feedback on the screening experience was collected by survey. Data were collected in June and July 2017; data from August 2017 will be available for presentation.

Result:
The majority (87%) of the 862 people recruited into the pilot were provider-referred. Of the 472 people who completed a risk assessment, 71% were found to be eligible for screening (PLCO~M2012noRace~ 6-year risk ≥2.0%). Baseline LDCT scans were conducted for 156 participants; approximately 8% of these participants were referred to a DAP for further assessment. Uptake of smoking cessation services by current smokers was high (data to be included in presentation). Feedback surveys were received from 78 of 156 participants screened. Overall experience with the screening visit was rated as ‘excellent’ by 91% of respondents, and 70% indicated a preference to receive results during the same visit as the LDCT.

Conclusion:
Provider-led recruitment supports the identification of screen-eligible individuals. Implementation of navigator-guided organized screening, following a detailed screening pathway that features provision of same-visit results, has contributed to high participant satisfaction to date. To our knowledge, this pilot involves the most detailed organized screening pathway and comprehensive evaluation plan developed to date. Learnings from this pilot will be highly relevant to jurisdictions around the world that are adopting screening.

Abstract not provided

Background:
Liquid biopsy is a promising approach to improve the management of NSCLC patients, offering a minimally-invasive alternative to tumor tissue testing and enabling timely monitoring of patients on-therapy. The goal of the present study was to evaluate the performance of the OncoBEAM EGFR plasma vs EGFR tissue testing across 19 Spanish hospitals and to examine the timing of T790M mutation emergence in patients during first-line EGFR TKI therapy with respect to radiological progression.

Method:
Blood samples from 112 therapy-naïve advanced NSCLC patients were collected at baseline and throughout EGFR TKI therapy. Results from OncoBEAM EGFR mutation were performed by Sysmex in Hamburg, Germany and then compared to those obtained by the initial EGFR tissue testing obtained at the referring hospital. In addition, the time at which T790M was first detected was compared to the date of progression determined by radiological imaging.

Result:
112 stage IV NSCLC patients (p) were enrolled between Nov 2016 and May 2017. Clinical characteristics: median age 65 y. , 81 female. Smoking pattern: never 70 p (62,5%), former 33 p (29.4%) and active 9 (8%). M1a 28 p (25%), M1b only brain 10 p (8.9%), only bone 17 p (15%). Baseline tissue samples: Exon 19 deletion 74 p (66%) , L858R 38 p (34%). Initial positive percent agreement (PPA) in 69 out of 112 p was 52/69 or 75.4%. Interestingly, the agreement between plasma and tissue EGFR mutation results for patients diagnosed at M0 was 56%, versus 81% with patients diagnosed at M1. In addition, the average number of days between tissue biopsy and blood collection for concordant cases was 128 days, versus 358 days for discordant cases. Currently, the tissue EGFR mutation status of all discordant cases is being re-examined using BEAMing. Preliminary results from serial T790M plasma analyses revealed cases where detection by OncoBEAM was observed several weeks prior to documented progression by imaging. More mature results will be available at the time of the meeting

Conclusion:
Overall, these initial results show high PPA of plasma and tissue EGFR mutation status at baseline. Moreover, early detection of T790M in blood may assist in anticipating resistance to first-line EGFR TKI therapy.

Background:
Next-generation sequencing (NGS) of cell-free DNA (cfDNA) in plasma can be an alternative or complement to tissue biopsy for genomic analysis of non-small cell lung cancer (NSCLC), particularly for identifying driver and resistance alterations. We presented preliminary data in 67 patients comparing NGS in plasma vs. tissue (Santos et al. JTO; 11:10, S199-200) and found EGFR mutation agreement of 68% between plasma and tissue. We now present an expanded patient cohort with more extensive concordance analysis, longer follow-up, and clinical outcomes.

Method:
We analyzed data from advanced (stage III/IV) NSCLC patients seen at three cancer centers in Florida (US; Memorial Cancer Institute, Florida Hospital Cancer Center, Mount Sinai Cancer Center) that had alterations detected on Guardant360 (G360) testing through January 2017. G360 is a plasma cfDNA NGS assay that detects single nucleotide variations, amplifications, fusions, and indels in targeted genes using massively parallel digital sequencing; panel composition expanded from 54 to 73 genes over the course of the cohort. NGS performed on solid tumor biopsies from each subject were reviewed for comparison where available but may not have been collected contemporaneously to the plasma samples. Treatment information and clinical outcomes were collected for those patients with actionable mutations per NCCN guidelines (v3.2017).

Result:
A total of 190 G360 test results on 171 unique patients were identified (some patients underwent serial testing at multiple clinical timepoints, e.g. progression). Forty percent of patients were male; the median age was 65 (32-94). Excluding variants of uncertain significance, patients were most likely to have cfDNA alterations in TP53 (44%), EGFR (21%), KRAS (19%), BRAF (8%), and MET (8%). Forty-seven patients (28%) had at least one actionable mutation identified on G360, including SNVs, indels, fusions, and amplifications. Preliminary clinical outcomes data include durable (³10 months) partial responses on targeted therapy based on multiple plasma-detected alterations in EGFR and BRAF V600E; complete analysis will be presented at the meeting.

Conclusion:
Liquid biopsy plays an important role in genomic analysis of NSCLC, offering reliable information to guide therapeutic decision-making. Results in our cohort include a noteworthy proportion of patients with highly actionable mutations, like EGFR drivers and targetable resistance mutations, and G360 offers an alternative to tissue biopsy in these patients.

Background:
Circulating tumor DNA (ctDNA), extracted from plasma, is a non-invasive surrogate biomarker. However, the distribution of ctDNA in the body still remains to be elucidated. In this study, resected lung tumors, with simultaneous blood and bone marrow samples, were analyzed to elucidate the distribution of ctDNA.

Method:
Rib bone marrow, pulmonary venous blood (Pul.V) and peripheral blood (Peri.B) were obtained from 30 patients. The liquid samples were divided into cell pellets and supernatant by centrifugation; a total of 212 DNA samples were subjected to massively parallel sequencing.

Result:
ctDNA was detected in 5 patients. Given that the frequency of mutations in the primary tumor was considered to be 100%, those in the other specimens were as follows; Pul.V plasma 20%, Peri.B plasma 11%, and the other samples 0%. Furthermore, ctDNA reflected the predominant mutations in the primary lesion. Clinically, the presence of ctDNA was associated with significantly poorer survival.

Conclusion:
These results suggest ctDNA “spill over” into an immediate outflow tract (Pul.V), and from there is disseminated to the entire body. Thus, it can be inferred that ctDNA reflects the cancer progression and could function as a prognostic marker.

Background:
The ALK rearrangement (ALK+) is an important actionable genetic aberration of NSCLC, which is associated with high sensitivity to targeted agents such as crizotinib and alectinib. Currently, ALK+ is mainly detected by fluorescent in situ hybridization (FISH) or immunohistochemistry that strictly require the availability of tumor sample, however, in NSCLC, tumor tissue are not always valid or sufficient for testing and non-invasive analyzing methods are urgently needed. Recent years, next generation sequencing (NGS) based liquid biopsy has emerged as a useful complementary technique for the analysis of cancer genetic profile, in the present study, we aimed to evaluate the performance of liquid biopsy for the detection of ALK rearrangements in NSCLC.

Method:
From January 2016 to May 2017, paired tumor and cell-free plasma samples were collected form 360 histologically proven NSCLC patients. The presence of ALK+ was detected by fluorescent in situ hybridization (FISH) in tumor samples and by a NGS based liquid biopsy technology that targeted 96 genes, including ALK, in plasma samples. Genomic alterations in cancer-associated somatic variants are analyzed by massively parallel sequencing. The FISH results were set as golden-standard for the presence of ALK+. The specificity and sensitivity of liquid biopsy for the detection of ALK+ were evaluated.

Result:
ALK+ were detected in 28/360 (7.8%) of the tumor samples and 25/360 (6.9%) of the plasma samples. All the 25 ALK+ plasma samples were also ALK+ in their corresponding tumor samples. Liquid biopsy failed to detect ALK+ in 3 samples that were positive in tumor sample. Thus, the specificity and sensitivity of liquid biopsy for detection of ALK+ in plasma were 100% and 89.3%, respectively.

Conclusion:
NGS based liquid biopsy technology is a promising, non-invasive method for the detection of ALK rearrangement that may benefit NSCLC patients who have difficult to obtain tumor samples or need continuous monitor of ALK status.

Abstract not provided

Background:
ERBB Receptor Feedback Inhibitor-1 (ERRFI-1) encodes MIG6, which is a negative regulator of EGFR and ERBB2 signaling. Loss of function alterations at ERRFI-1 would be expected to promote oncogenesis, but the role of ERRFI-1 alterations in conferring sensitivity to targeted therapies remains to be fully investigated.

Method:
We reviewed 19,347 cases of NSCLC in the Foundation Medicine data base for ERRFI-1 alterations that had been previously assayed by hybrid-capture based genomic DNA profiling of FFPE tissue specimens. Two patients, so identified, had been treated with EGFR pathway antagonist therapies and their outcomes are reported herein.

Result:
ERRFI-1 truncating mutations were identified in 0.62 % (120/ 19,347) of all screened NSCLC specimens. ERRFI-1 alterations were seen in all NSCLC histologic subtypes examined at similar frequencies: adenocarcinoma (0.7%), squamous carcinoma (0.3%), large cell carcinomas (0.8%), adenosquamous (0.6%), sarcomatoid (0.6%), and not otherwise specified (0.6%). Co-existing alterations included: P53 (59%), KRAS (19%), EGFR exon 19 del (9.2%), EGFR L858R (3.3%), EGFR T790M (3.3%), EGFR amp (6.7%), ERBB2 mut (7.5%), and ERBB2 amp (3.3%). Two female patients with ERRFI-1 mutations who were wildtype for known NSCLC driver mutations and targeted therapy naive, achieved RECIST criteria partial responses after treatment with single agent EGFR TKI therapies. Following subsequent disease progression, one of these patients also achieved a secondary response to single agent EGFR directed monoclonal antibody therapy. To our knowledge, these are the first two reported patient outcomes for targeted therapies in ERRFI-1 altered NSCLC.

Conclusion:
The index cases presented here suggest that NSCLC patients with genetic lesions in ERRFI-1 may respond to both anti-EGFR TKIs and monoclonal antibodies. However, co-occurrence between ERFFI-1 mutations and alterations in known NSCLC drivers such as EGFR exon 19 del and L858R may also indicate that in some contexts, ERRFI-1 alterations may provide a mechanism for acquired resistance to targeted therapies as well. Further investigation including assessment of ERRFI-1 loss of heterozygosity, ERRFI-1 VUSs , and clinical evaluation of additional cases including response and resistance to targeted therapy will be performed to more fully delineate the role of ERRFI-1 in NSCLC.

Background:
Remarkable advances for clinical diagnosis and treatment in cancers including lung cancer involve cell-free circulating tumor DNA (ctDNA) detection through next generation sequencing. However, before the sensitivity and specificity of ctDNA detection can be widely recognized, the consistency of mutations in tumor tissue and ctDNA should be evaluated. The urgency of this consistency is extremely obvious in lung cancer to which great attention has been paid to in liquid biopsy field.

Method:
Averagely 10 ml preoperative blood samples were collected from 30 patients containing pulmonary space occupying pathological changes by traditional clinic diagnosis. cfDNA from plasma, genomic DNA from white blood cells, and genomic DNA from solid tumor of above patients were extracted and constructed as libraries for each sample before subjected to sequencing by a panel contains 50 cancer-associated genes covering 1654 hotspots by custom probe hybridization capture with average depth >40000, 7000, or 6300 folds respectively.

Result:
Detection limit for mutant allele frequency in our study was 0.1%. The sequencing results were analyzed by bioinformatic expertise based on our previous studies on the baseline mutation profiling of circulating cell-free DNA and the clinicopathological data of these patients. Among all the 27 lung cancer patients, 80 percent were predicted as positive by ctDNA sequencing when the standard was defined as at least one of the hotspot mutations detected in the blood (ctDNA) was also detected in tumor tissue. Pneumonia and pulmonary tuberculosis were detected as negative according to the above standard. When evaluating all hotspots, 949 of 1265 (75 percent) mutations detected in tumor tissue were also detected in patients' blood. When evaluating all genetic variations, including those present at high levels in tumor tissue (clonal, driver genes in the panel) as well as those at low levels (subclonal, passenger genes in the panel), 327 of 583 (56 percent) detected in tumor tissue were also detected in patients' blood. Mutations detected only in blood (ctDNA and genomic DNA in white blood cells) but not in tumor tissue are not well understood yet.

Conclusion:
We demonstrated the importance of sequencing both circulating cell-free DNA and genomic DNA in tumor tissue for ctDNA detection in lung cancer. We also determined and confirmed the consistency of ctDNA and tumor tissue through NGS according to the criteria explored in our studies. Our strategy can initially distinguish the lung cancer from other space occupying lesions of lung. Our work shows that the consistency will be benefited from the optimization in sensitivity and specificity in ctDNA detection.

Background:
Limited and conflicting data are available for the safety and clinical efficacy of EGFR TKIs, especially third-generation TKI osimertinib, in the rare (<0.1%) subset of NSCLC patients carrying a germline EGFR T790M mutation. We here report a patient with concurrent somatic EGFR L858R and germline EGFR T790M mutations detected by liquid biopsy and tumor genomic profiling assay.

Method:
A 67-year-old male, life-long never smoker was initially found to have bilateral, small lung nodules incidentally on a CT scan during the workup for a kidney stone. His family history suggests a hereditary predisposition to lung cancer given there were three other individuals (including two never smokers) across three generations with a history of lung cancer. The patient underwent annual surveillance chest CT scans over a two-year period before a biopsy-proven stage IA lung adenocarcinoma was found, which was treated with stereotactic body radiation. Unfortunately, this patient developed local tumor recurrence in the lung and wide spread bony metastases in less than one year. To determine the effect of EGFR TKIs on normal blood cells, we established a permanent Epstein-Barr Virus (EBV)-transformed lymphoblastoid cell line from the patient’s peripheral blood mononuclear cells (PBMCs) and determined the in vitro cytotoxicity of the cell line to first, second, and third generation EGFR TKIs. Serial tumor genomic profiling of plasma ctDNA by the Guardant360 assay was obtained each time clinical treatment was changed for this patient.

Result:
We found neither EGFR nor AKT expression in the PBMCs and the EBV-transformed lymphoblastoid cell line established from this patient. The EBV-transformed lymphoblastoid cells were resistant to all first, second and third generation EGFR TKIs tested. This patient achieved rapid clinical response to osimertinib after progression on radiation, chemotherapy, and afatinib. Serial genotyping of plasma ctDNA showed the alteration of EGFR L858R level correlated with tumor response while the mutant allelic frequency of EGFR T790M remained at ~50%. A heterozygous EGFR T790M germline mutation was confirmed by genetic testing.

Conclusion:
To our knowledge, this is the first combined in vitro and clinical data supporting the safety and efficacy of osimertinib in patients with the germline EGFR T790M mutation. Further mechanistic studies are needed to understand the tumorigenesis and clinical management for lung cancer patients and carriers with a germline EGFR T790M mutation.

Background:
The prognostic impact of the presence of tumor spread through air spaces (STAS) has been reported in lung adenocarcinoma (ADC). The aim of this study is to investigate the prognostic impact of the distribution, distance from the primary tumor, and quantification of STAS.

Method:
A cohort of 394 patients with pathologic stage I lung ADC (2012-2014) were investigated. The distribution of STAS around the tumor was classified into focal or circumferential. The distance of STAS was evaluated by counting the number of air spaces between the farthest STAS and the tumor edge. STAS was quantified by counting the number of STAS areas in the three most STAS- dense 20x high power fields (HPFs). The recurrence free probability (RFP) was analyzed by the Kaplan-Meier method with a log-rank test.

Result:
STAS was present in 211 (54%) cases. The presence of STAS was associated with a higher risk of recurrence (5-y RFP in STAS-positive vs. STAS-negative; 78% vs 90%, p<0.001, Fig 1A). Circumferential STAS was associated with a higher risk of recurrence than focal STAS (5-y RFP in circumferential vs. focal; 67% vs 87%, p=0.027, Fig 1B). A longer distance of STAS was associated with a higher risk of recurrence (5-y RFP >7 alveoli vs.≤7 alveoli, 69% vs. 91%, p=0.003, Fig 1C). Quantification of STAS was not prognostic (5-y RFP in >3/HPFs vs. ≤3/HPFs, 75% vs. 88 %, p=0.15). Figure 1 X



Conclusion:
Beyond just the presence of STAS, the distribution and distance of STAS can further stratify the risk of recurrence in stage I lung ADC.

Abstract not provided

Background:
Bevacizumab (Bev; Avastin[®]) is a monoclonal antibody against the vascular endothelial growth factor. No predictive biomarkers for the use of Bev have been established so far. We aimed identifying genes predictive for progression-free survival (PFS) and overall survival (OS) of patients treated in the trial SAKK19/09 (NCT01116219).

Method:
SAKK19/09 was a non-randomized phase II trial with two sequential cohorts including patients with non-squamous NSCLC and EGFR wild-type. In Cohort 1, 77 patients were treated with cisplatin (C) 75mg/m[2], pemetrexed (Pem) 500mg/m[2] and Bev 7.5mg/kg, followed by Bev+Pem maintenance. Cohort 2 included 52 patients treated with C+Pem followed by Pem maintenance. RNA was isolated from baseline tumor tissue sections and processed for gene expression analysis by Nanostring. Using the Nanostring nCounter® System (Nanostring Technologies) gene expression of 201 genes, including 6 housekeeping genes was measured using a custom-designed codeset. For each gene, a Cox regression was performed with normalized gene expressions, treatment and the interaction for PFS and OS. No adjustment for multiple testing was done.

Result:

Gene	Accession	HR (95% confidence interval)		p-value of interaction
		Cohort 1	Cohort 2
Potential predictive markers for PFS
AURKB	NM_004217	1.09 (0.84-1.42)	0.78 (0.61-0.99)	0.0481
CCNE1	NM_001238	1.09 (0.87-1.36)	0.73 (0.53-1.02)	0.0312
CDKN2B	NM_004936.3	0.80 (0.67-0.95)	1.10 (0.85-1.43)	0.0375
MMP2	NM_004530.2	0.81 (0.67-0.97)	1.10 (0.91-1.34)	0.0258
PTGS2 (COX-2)	NM_000963.1	1.29 (1.06-1.58)	0.90 (0.78-1.04)	0.00352
TGFA	NM_003236.2	1.13 (0.94-1.37)	0.74 (0.53-1.03)	0.0452
WISP2	NM_003881.2	0.82 (0.69-0.98)	1.24 (1.02-1.51)	0.0015
Potential predictive markers for OS
CCNE1	NM_001238	1.08 (0.86-1.36)	0.71 (0.49-1.02)	0.0324
PTGS2 (COX-2)	NM_000963.1	1.35 (1.10-1.65)	0.81 (0.69-0.95)	<0.0001
TGFA	NM_003236.2	1.17 (0.96-1.43)	0.55 (0.33-0.91)	0.00352
WISP2	NM_003881.2	0.87 (0.73-1.03)	1.14 (0.92-1.42)	0.0314

We analyzed 99 patient samples (61 in Cohort 1; 38 in Cohort 2) with 201 genes at baseline. We found 7 genes potentially predictive for PFS (AURKB, CCNE1, CDKN2B, MMP2, PTGS2, TGFA, WISP2), 4 of which were also potentially predictive for OS (CCNE1, PTGS2, TGFA and WISP2) (Table 1).

Conclusion:
We identified several potentially predictive genes for Bev activity in combination with chemotherapy. Several of these (AURKB, CCNE1, CDKN2B, TGFA) have previously been shown to play an important role in cell cycle regulation and cell proliferation supporting the hypothesis that Bev supports chemotherapy activity. Notably, also a gene involved in inflammation (PTGS2) was significantly predictive for outcome. Further work is ongoing to explore changes in gene expression using tumor rebiopsies at progression.

Background:
MicroRNAs (miRNAs) are key regulators of gene expression. They participate in many biological and pathological processes, from organ development to malignant transformation. Their functions are widely conserved, involving post-transcriptional silencing of gene expression. Over 2500 mature miRNA sequences have been identified in humans; however, recent studies have showed that the number of annotated miRNAs represent only a fraction of the total pool of existing miRNAs, suggesting that there are still many potentially undiscovered biologically relevant miRNAs encoded by the human genome. Here, we perform a comprehensive study to identify novel miRNA sequences expressed in non-malignant lung tissues, as well as samples from developmental stages and pathological conditions.

Method:
A total of 422 samples were included in this analysis. First, 209 non-malignant samples from two cohorts (BCCA, n=118 and TCGA, n=91) were analyzed using our customized small RNA sequence analysis pipeline. Sequence reads were aligned to the hg38 build of the human genome (STAR algorithm) and novel miRNAs were predicted using mirDeep2. The results were compared to miRNA databases and further filtered by abundance and for miRNA-compatible structure. The same procedure was applied to matched tumours (n=209) and samples derived from fetal lungs (n=4). The biological relevance of the novel sequences was investigated by assessing their expression in tumours and fetal samples, together with gene target prediction and tissue-specific protein-protein interaction (PPI) network analyses using IID.

Result:
Our study discovered the expression of 294 novel miRNA sequences in lung tissue, significantly expanding the current human lung miRNA transcriptome. These novel miRNAs showed similar nucleotide composition and genomic distribution compared to known miRNAs, providing additional evidence of their miRNA-compatible nature. Interestingly, a subset of these miRNAs were also found to be expressed in tumour and fetal samples, indicating that they might play important roles in organ development and tumourigenesis. Likewise, target prediction analysis revealed that these novel miRNAs are involved in key cellular processes including cell proliferation, migration and survival, as well as pathways known to be deregulated in cancer, as comprehensively analyzed using pathDIP.

Conclusion:
Our study has significantly expanded the lung small RNA transcriptome, and provided evidence that the novel miRNAs are involved in molecular networks relevant to lung biology and pathology. These results also highlight their specific roles in developmental regulation and malignant transformation, suggesting their role as biological regulators and implicating their potential as therapeutic targets.

Background:
Cancer-derived exosomes are micro-vesicles released by tumor cells and are believed to be involved in intercellular signaling and communication. Recent evidence suggests exosomes help tumor cells invade neighboring tissues and prime metastatic sites for disease spread. Non-small cell lung cancer (NSCLC) is a highly metastatic disease and little is known about how tumor-derived exosomes may influence migration or invasion of lung cancer cells and prime metastatic niches.

Method:
Exosomes were recovered by a sequential centrifugation schema. Exosomes isolated from lung cancer cell line H1299, A549, H1993, and H2073, and non-malignant, immortalized human bronchial epithelial cell (HBEC) 3KT and 30KT were characterized. We examined the effects of cancer-derived exosomes on HBECs, oncogenically progressed HBECs (HBEC sh-p53+KRAS[v12]; HBEC3KTRL53) in vitro and their influence on metastasis in murine models. Mass spectrometry was performed to identify candidate proteins carried in tumor exosomes that induce phenotypic changes in recipient cells.

Result:
Cancer-derived exosomes but not HBEC-derived exosomes confer invasiveness and increased motility on recipient cells (HBEC3KT, HBEC3KTRL53) in wound healing and Boyden chamber assays. Mesenchymal NSCLC exosomes induce mesenchymal-like phenotypic changes (loss of EPCAM expression and upregulated EMT-transcriptional factors) in HBEC3KT in FACS and qRT-PCR analyses. Cancer-derived exosomes but not HBEC3KT exosomes enhance the lung endothelial permeability, promote lung metastasis, and recruit myeloid-derived suppressor cells in vivo. Mass spectrometry shows that H1299 exosomes contains a wide variety of deubiquitinating enzymes (DUBs) compared to HBEC3KT exosomes, and UCHL-1 (Ubiquitin carboxy-terminal hydrolase L1) is the most highly expressed DUB in H1299 exosomes. UCHL-1 expression is upregulated in mesenchymal NSCLC cells/exosomes, and HBEC3KT cells treated with mesenchymal NSCLC exosomes in vitro, and activated in metastatic sites after cancer-derived exosome treatment in vivo. UCHL-1 knockdown suppresses metastasis induced by cancer-derived exosomes. Exosomes derived from UCHL-1-knockdown H1299 show a decreased effect of the induction of migration, invasiveness, and epithelial/mesenchymal phenotypic changes on recipient cells.

Conclusion:
Mesenchymal NSCLCs-derived exosomes compared to HBECs-derived exosomes induced an increased migratory/invasive phenotype with lung vascular leakiness, metastatic niche formation, and higher xenograft tumor take rates. UHCL-1 was overexpressed only in mesenchymal NSCLCs/exosomes. UCHL-1 knockdown suppressed metastasis, and its exosomes also showed a decreased effect of the induction of tumor progression. These results suggest that understanding and targeting UCHL-1 likely as a key factor of mesenchymal NSCLC-derived exosome behavior could lead to novel therapeutic strategies.

Background:
Identifying the drivers of metastasis will yield new molecular targets for prognostics and therapeutics. Long non-coding RNAs (lncRNAs) are known to regulate gene transcription through their influence on the expression of nearby (cis) and distant (trans) genes. Emerging evidence suggests that lncRNAs are involved in key cellular processes, presenting an opportunity for large-scale identification of lncRNA genes critical to lung cancer progression. Here we investigate the contribution of this class of non-coding RNA to lung adenocarcinoma (LUAD) metastasis.

Method:
Stage T1 and T2 tumours with (N≥1 and/or M≥1) and without (N=0 and M=0) metastasis were examined for expression comparisons. Sequencing data from 265 non-metastatic and 130 metastatic tumours obtained from The Cancer Genome Atlas were used as our discovery cohort. Results were validated in 20 non-metastatic and 10 metastatic tumour samples microdissected to 90% purity and sequenced using the Illumina Hi-Seq platform. Normalized sequence read count comparisons were performed (Mann Whitney U-Test, FDR-BH p<0.05) to identify lncRNAs significantly deregulated in metastatic samples. LncRNAs over- and under-expressed in metastatic LUAD were compared to nearby protein-coding-target genes to identify putative mechanisms of regulation in cis.

Result:
We discovered 150 lncRNAs to be significantly differentially expressed between metastatic and non-metastatic tumours, including lncRNAs with previously described oncogenic roles in lung cancer, such as Lung Cancer Associated Transcript 1 and H19. As individual lncRNAs can positively or negatively regulate target-gene expression, it is noteworthy that we identified potential protein-coding-target genes that display both concordant and discordant expression patterns with specific lncRNAs. For example, we discovered the upregulation of linc00942 in metastatic LUAD (FDR-BH p=0.001) and the concordant overexpression of its corresponding protein-coding-target gene, ELKS/RAB6-Interacting/CAST Family Member 1 (ERC1) (FDR-BH p=0.02). Further, metastatic LUAD samples stratified by linc00942 expression also display corresponding elevation of ERC1 (p=0.0002), which holds true in the validation cohort. ERC1 (an upstream member of the NF-κB signaling pathway) is implicated in cell migration and focal adhesion, and displays deregulated expression in a number of cancer types. Thus, overexpression of linc00942 may act as a novel positive cis-regulator of ERC1, promoting metastasis.

Conclusion:
This work has led to the discovery of a large number of lncRNA genes deregulated in metastatic LUAD, suggesting that altered lncRNA expression contributes functionally to malignant progression. Understanding cis- or trans-mediated mechanisms of gene deregulation enacted by metastasis-associated lncRNAs will present novel opportunities for diagnosis and treatment.

Abstract not provided

Background:
Thymomas are frequently associated with paraneoplastic autoimmune syndromes, with the most common being Myasthenia Gravis (MG). MG is characterized by autoantibodies against muscle antigens, most frequently the acetylcholine receptor (AChR). Patients with thymoma also present with autoantibodies against striational muscle proteins (STR-Abs), such as the sarcomeric protein titin and the ryanodine receptor. These autoantibodies have been primarily regarded as diagnostic or prognostic markers, but little is known about their pathological mechanisms. Comprehensive mechanistic studies have been hindered by the lack of patient-derived monoclonal antibodies (mAbs). Such mAbs could help to define immunogenic epitopes in known or novel autoantigens, and would be useful for deciphering pathological mechanisms in vitro or in animal models.

Method:
We studied mAbs derived from a patient with thymoma and MG, with the patient’s written informed consent and under a Stanford IRB approved protocol. The patient had Masaoka-Koga stage II type B2 thymoma, with multiple recurrences over a period of 8 years. The patient’s MG symptoms included fatigable muscle weakness, the presence of anti-AChR antibodies, and high titer STR-Abs. The patient also had myositis with muscle-related symptoms worsening after thymectomy. We sequenced the repertoire of the patient’s plasmablasts, which are antibody-producing cells derived from the activated B-cell clones, using a barcode-based method for sequencing single-cell immunoglobulin genes developed in our lab. We then expressed 26 mAbs from clonally expanded families of antibodies from two different timepoints that are six months apart. The first timepoint was two years post-Rituximab, coinciding with a tumor recurrence and slow progression of muscle weakness. The second timepoint was a month after radiotherapy when the patient was admitted with severe muscle weakness and pain. Treatment included plasmapheresis/IVIG and Rituximab, with limited improvement over the weeks following hospitalization. The patient was on steroids at both timepoints. Anti-Titin serum antibody titers increased by 60% between these two timepoints.

Result:
Two of the mAbs that were expressed reacted with the main immunogenic region of titin in ELISA, and one of the clones was present at both of the timepoints investigated. These clones were detected despite B-cell depletion by treatment with Rituximab.

Conclusion:
Our results suggest that (i) sequencing single-cell immunoglobulins is a powerful technique for isolating and functionally characterizing mAbs against autoantigens in thymoma and that (ii) persisting or recurring autoreactive clones in patients with thymoma, such as anti-titin clones, may be associated with refractory paraneoplastic syndromes despite use of immunosuppressive therapies.

Background:
The immune checkpoint ligand programmed cell death 1 ligand (PD-L1) is expressed in various tumors, and the expression of indoleamine 2,3-dioxygenase (IDO) and Foxp3 Tregs are associated with tumor-induced tolerance and reported to be responsible for worse survival. Their prognostic role in thymoma and thymic carcinoma, however, has not been investigated.

Method:
A tissue microarray comprised of 100 surgically treated thymomas and 69 surgically treated thymic carcinomas was evaluated. PD-L1, IDO, and Foxp3 Treg staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. The PD-L1, IDO, and Foxp3 Treg expression score was calculated using a semiquantitive method by multiplying the intensity [0-3] by the staining area [0-100%]. Those cases with all cores scoring three and 2 in more than 50% in the staining area were categorized as PD-L1, IDO, and Foxp3 Treg high expression and the remaining as low expression. Clinical information was also collected on age, sex, Masaoka staging, tumor histology, surgical radicality, and locoregional invasion. Statistical associations were evaluated using χ[2] test and Fisher’s exact test. Progression-free survival and overall survival curves were established by the Kaplan-Meier method and compared using a log-rank test.

Result:
Figure 1Figure 2Thirty-six (36%) thymoma and 25 (36%) thymic carcinoma cases revealed high expression of PD-L1. PD-L1 expression in thymoma is significantly associated with Masaoka staging (p<0.001), tumor histology (p<0.001). Although there was a trend toward worse progression-free and overall survival in thymoma and thymic carcinoma with high-expression of PD-L1, only the progression-free survival in thymoma was significantly worse (p=0.024). High expression of IDO was detected in 13 (13%) thymoma and 10 (14%) thymic carcinoma cases, whereas Foxp3 Treg was detected in 16 thymoma (16%) and 20 (29%) thymic carcinoma cases. The expressions of IDO and Foxp3 Treg were significantly associated with tumor histology in thymoma (p=0.002 and 0.016, respectively), but not in thymic carcinoma. Thymic carcinoma with high expression of IDO had a trend toward worse progression-free and overall survival trend (p=0.109 and 0.053, respectively). High expression of Foxp3 Treg, however, was significantly associated with better progression-free survival (p=0.006) and overall survival (p=0.007) in thymic carcinoma.





Conclusion:
This is the largest-scale study to evaluate PD-L1 expression in thymic epithelial tumors. Although high expression of PD-L1 might be associated with worse prognosis in thymoma and thymic carcinoma, further investigation into PD-L1, IDO, and Foxp3 Treg should be conducted to benefit anti-PD-L1 immunotherapy for thymic epithelial tumor.

Background:
The management of patients with locally advanced thymic malignancies remains controversial. Various combinations of surgical resection, chemotherapy and radiation are currently used. Given the generally favorable prognosis, treatment related toxicities and quality of life (QOL) could inform therapeutic options. For economic analyses, QOL can be measured as health utilities. This study describes health utility scores (HUS) in patients with locally advanced thymic malignancies, while determining the impact of multimodality regimens on HUS.

Method:
In a cross-sectional study (2014-2017), patients with Masaoka stage II-IVa thymic malignancies seen at a comprehensive cancer centre completed various self-reported questionnaires at routine medical visits. HUS as measured by the EuroQol-5-Dimensions (EQ-5D) with visual analogue scale (VAS) and self-reported Eastern Cooperative Oncology Group (ECOG) performance status were compared in patients treated with trimodality versus uni- or bimodality regimens. Patient-reported Edmonton Symptom Assessment Scale (ESAS) scores were also collected to explore symptom burden. Regression analysis was used to compare groups; multivariable analysis investigating potential confounders was also conducted.

Result:
From 2014 to 2017, 72 patients were included in the study; 43 (59.7%) were male with a median age of 58 years, 65 (90.3%) had thymoma while 7 (9.7%) had thymic carcinomas and median time since diagnosis was 50.5 months (range: 3-266). Compared to patients treated with uni/bimodality regimens (n=48), those treated with trimodality (n=24) had higher stage of disease at diagnosis and were more likely to have received multiple lines of chemotherapy. Median HUS and VAS did not differ between groups (trimodality vs uni/bimodality: HUS=0.77 vs 0.80, p=0.26; and VAS=80 vs 75, p=0.79, respectively). The distribution of patient-reported ECOG at assessment was also similar (p=1.00). ESAS scores for pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, wellbeing and shortness of breath were neither statistically nor clinically different by number of modalities of therapy. Subset analyses of individuals who were 1+ year since diagnosis affirmed these findings.

Conclusion:
Patients with stage II-IVa thymic malignancies report favorable HUS, VAS and self-reported ECOG with minimal symptom burden. Trimodality therapy appears similarly tolerable when compared to uni- and bimodality regimens in this population.

Background:
Thymic carcinoma (TC) is a rare cancer with minimal evidence of survival with palliative-intent chemotherapy. Sunitinib and everolimus monotherapies have been proposed as active molecular-targeted approaches based on phase II (Ph II) trials, and S-1, an oral fluoropyrimidine, has been described in the NCCN guideline as an active cytotoxic agent for refractory TC based on a case series. Therefore, we conducted a Ph II trial to study the result of S-1 treatment in patients with refractory TC.

Method:
In this Ph II study performed at three cancer centers in Tokyo, we aimed to enroll 26 TC patients previously treated with platinum-based chemotherapy. The patients received S-1 orally twice daily at a dose of 40–60 mg/m2 for 4 weeks, followed by 2 weeks off until progressive disease or unacceptable toxicities. S-1 was used off-label. The primary end-point was determining the objective response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.

Result:
Twenty-six patients (10 males) were recruited between November 2013 and May 2016. The median age was 63 (27–74) years. Among the 26 patients, 23 had squamous cell carcinoma histology and 10 had an ECOG performance status of 0. Additionally, one patient showed complete response and seven patients showed partial responses, resulting in a 30.8% response rate (95% confidence interval [CI], 16.5–50.0) and a 65.4% disease control rate (95% CI, 46.2–80.6). After a median follow-up of 13.4 months, the median PFS was 4.3 months (95% CI, 2.3–7.6 months) and median OS was 23.4 months (95% CI, 12.8–not reached). Treatment-related adverse events (AEs) of grade ≥3 included neutropenia (12%), skin rash (8%), elevated ALT, decreased WBC count, and fatigue (4%). No treatment-related death was observed. However, treatment was discontinued in three patients (12%) because of AEs.

Conclusion:
S-1 for refractory TC confirmed clinical activity with good tolerability. Clinical trial identification: UMIN000010736

Abstract not provided

Background:
Conventionally, minimally invasive thymectomy for early-stage thymoma was performed via unilateral thoracoscopic approach. However it is sometimes criticized for bad exposure of anterior mediastinum which may be disadvantagous for the surgery. Recently, we attempted a modified subxiphoid thoracoscopic approach with novel sternal-elevating technique to reach better surgical exposure and less trauma.

Method:
From January 2015 to December 2016, a total of 83 consecutive patients with early-stage thymomas without myasthenia gravis were enrolled. Between them, 36 patients were performed thoracoscopic thymectomy via subxiphoid approach (Group S) . Three subxiphoid incisions (12mm*1, 5mm*2) with the aid of artificial CO~2~ pneumothorax (8cmH~2~O) were used. Additionally, we used the sternum-elevating device (Rul-tractor, USA) through the 3rd intercostal incision (5mm*1) beside the sternum. And the other 47 cases underwent conventional thymectomy via unilateral 3-port thoracoscopic approach (Group UL). The perioperative outcome of two groups were compared.

Result:
The two groups were comparable on patients[,] demographics. Conversion to open surgery occurred in 1 case (due to bleeding) in Group UL. Compared with Group UL, the patients in Group S had much shorter surgical duration [(63.5±10.7)min vs (87.7±13.1)min, p=0.000], much less pain scores (2.3±1.0 vs 3.1±1.30, p=0.002) and earlier pleural drainage removal [(1.6±0.6)d vs (2.3±0.9)d, p=0.000]. The complications were similar (5.6% vs 6.4%, p=0.758). No significant difference was found on the other outcomes between the two groups, including blood loss and postoperative hospital stay.

Conclusion:
This study suggests that the modified subxiphoid thoracoscopic approach seems to be more effective for thymectomy for early-stage thymomas. This novel approach could improve surgical exposure, accelerate the operative progress and result in less trauma and pain. It could be a promising refinement for future thymic surgery.

Background:
The co-existence of MG and thymoma makes the surgical treatment more complicated and adjuvant radiation more controversial. The aim of this article is to investigate whether patients with MG and thymoma should receive mediastinal radiation therapy and when after extended thymectomy.

Method:
Between 2003 and 2014, 181 patients with MG and thymoma underwent extended thymectomy. According to application of radiation therapy, these patients were divided into 2 groups: Group 1 (n=157), patients having mediastinal radiation therapy after surgery; Group 2, without adjuvant radiation therapy (n = 24). Group 1 was subdivided into 3 subgroups: 1-month subgroup(n = 98); 2-month subgroup(n = 7): and 3-month subgroup(n = 52).

Result:
There were no intraoperative deaths and no inoperable cases. 172 patients underwent extended thymectomy by video-assisted thoracoscopic surgery, and 9 undergoing the trans-sternal approach due to thymoma invading great vessels. There was no significant difference in the aspects, such as length of surgery, Operative complications, and ICU stay, between 1-month subgroup, 3-month subgroup and Group 2. The proportions of type A, AB, B1, B2, B3, and thymic carcinoma were 0.6%, 18.2%, 26.5%, 33.7%,21.0%, and 0%, respectively. There were no radiation-related deaths. 159 patients were followed for 15 months to 12 years. Postoperative myasthenic crisis occurred in 40 cases. There was a significant difference in occurrence of postoperative myasthenic crisis between 1-month subgroup and Group 2 (P=0.031). The rates of reaching CSR were 32.6% in 1-month subgroup, 25% in 3-month subgroup, and 22.7% in Group 2, respectively. Overall survival rates of 1-month subgroup, 3-month subgroup, and Group 2 were 88.8%, 83.3%, and 77.3%, respectively. Among 14 recurrences, 11 cases happened in pleural cavity; 2 recurrences in lung; and one patient having metastasis to liver. There was no lymph node metastasis detected. Kaplan-Meier survival curves demonstrate that within 7 years after surgery, there is no significant difference in aspects of overall survival and disease-free survival between 1-month subgroup, 3-month subgroup and Group 2; over 8 years after surgery, disease-free survival rates in 1-month subgroup, 3-month subgroup and Group 2 were 79.4%, 70.6% and 55.3%, respectively.

Conclusion:
Adjuvant radiation within one month after extended thymectomy may be helpful in controlling postoperative MG, such as decreasing possibility of postoperative myasthenic crisis, and raising cumulative probabilities of reaching CSR. Whether it might have influence in prognosis of thymoma with MG needs to be further investigated in the future. In recurrences of thymoma patients with MG, no lymph node metastasis was detected

Background:
Surgical management of pleural dissemination of thymoma has been recommended in some reports, while reports on the long- term results of pleural dissemination resection are few. The aim of this study was to assess mid- and long- term results of surgical resection of pleural dissemination of thymoma.

Method:
We retrospectively analyzed data from patients with synchronous or metachronous pleural dissemination and primary thymoma who underwent surgical resection between 1996 and 2016 in our hospital.

Result:
During the study period, 38 patients underwent resection of pleural dissemination of thymoma. The synchronous group consisted of 21 patients with a median age of 50.2 years (range: 28—75 years) at the time of resection. The metachronous group consisted of 17 patients with a median age of 46.7 years (range: 30—65 years) at the time of resection of pleural dissemination. The median follow-up was 72.7 months (range: 3—248 months). In the synchronous group, 19 patients were in stage IVa and 2 patients were in stage IVb. The histological type of thymoma was type B1 in 3 patients, type B2 in 9 patients, typeB3 in 9 patients. In the metachronous group, Masaoka stage of the primary thymoma was as follows; 3 patients were in stage I, 5 patients were in stage II, 7 patients were in stage III and 2 patients were in stage IVb. The histological types of the resected dissemination nodule were type AB in 1 patient, type B1 in 1 patient, type B2 in 5 patients, and typeB3 in 10 patients. A macroscopic complete resection of pleural dissemination was achieved in 30 patients (79%) of all the patients. No perioperative deaths occured. Postoperative complications occurred in 5 patients (13.2%). During the observation period, 5 patients died (relation to the tumor in 4) in the synchronous group and 1 patient died (unrelated to the tumor) in the metachronous group. The 5- and 10-year overall survival rates of all the patients were 87.6% and 69.2%, respectively. Of all the patients, 14 received repeated resection of the pleural disseminated nodule. The 5- and 10-year overall survival rates from the first resection of pleural dissemination were 76.6% and 46.0% in the non-repeat resection group and 100% and 88.9% in the repeat resection group, respectively.

Conclusion:
Surgery for pleural dissemination of thymoma was safely performed and　provides favorable prognosis. Repeat resection for pleural dissemination could be effective in achieving a prolonged survival.

Abstract not provided

Background:
Primary mediastinal malignant germ cell tumors (GCT) are rare neoplasms with various histopathological findings and contain complicated clinical characteristics. Chemotherapy plays an important role in the treatment and there are some cases where a good prognosis is expected with multimodal treatment including surgical resection, pre- and postoperative chemoradiotherapy.

Method:
The medical records of 27 patients who were treated in our institution between 1988 and 2014 were retrospectively reviewed. We investigated the clinical characteristics and the outcomes of treatment.

Result:
All patients were male with a mean age of 30.7 years (range, 16-53 years), including 17 cases of seminoma (SGCT group) and 10 cases of non-seminoma (NSGCT group). Twenty-three patients underwent surgery and the remaining four patients received chemotherapy and/or radiotherapy without surgery. Of the 23 patients who underwent surgery, 17 cases received preoperative chemotherapy and 15 cases were treated with postoperative chemo/radiotherapy. In six patients, surgery was performed without preoperative chemotherapy due to the suspicious of thymoma, and was followed by postoperative chemo/radiotherapy. Among 24 patients whose serum tumor marker levels were measured before the treatment, 15 patients showed elevated serum tumor marker levels [five (35.7%) in SGCT group and 10 (100.0%) in NSGCT group]. Furthermore, among 20 patients whose serum tumor marker levels were measured before surgery, four patients showed elevated serum tumor marker levels [one (9.1%) in SGCT group and three (33.3%) in NSGCT group]. The median follow-up period after the treatment was 68 months (range, 4-316 months). The 5-year and 10-year survival rate was 88% and 88% in SGCT group, respectively, and 60% and 45% in NSGCT group, respectively (p=0.031). Although there was no relationship between the serum tumor marker levels before the treatment and the prognosis, the patients without elevated tumor marker levels revealed better prognosis than those with elevated one (p=0.014).

Conclusion:
The treatment for mediastinal malignant GCT in our institution was feasible with favorable outcomes. Although malignant GCT has poor prognosis especially in NSGCT group, chemotherapy which normalizes serum tumor marker levels can improve its prognosis.

Background:
Adenoid cystic carcinoma (ACC) of the trachea represents less than 1% of all respiratory tract cancers and lacks well-characterized molecular markers. There is no standard of care treatment for patients with recurrent and/or metastatic disease. The aim of this study is to identify and characterize novel, activating mutations in Notch receptors in ACC of the trachea and to determine response to Notch inhibitor Brontictuzumab.

Method:
Patients with ACC of the trachea at four institutions from 2011 through 2016 were identified. Target exome sequencing or analysis of hotspot mutations in cancer-related genes was performed by next-generation sequencing. Luciferase reporter assays were performed to confirm target gene expression in vitro. Patient-derived xenograft (PDX) models were sequenced, and Notch-mutant models were treated with Brontictuzumab. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation and inhibition by Brontictuzumab.

Result:
We showed that gain-of-function mutations of the Notch-1 gene in the PEST domain occurred in 10/62 tumors, leading to stabilization of the intracellular cleaved formed of Notch-1 (ICN1). Notch-1 mutations were associated with increased Notch-1 activation and its target gene HES-1. Mutations in Notch-2 (3/62), Notch-4 (3/62), Jagged-1 (2/62), FBXW-7 (4/62), and SPEN (1/62) were also identified in 13 (21.0%) patients. We observed a strong inverse correlation of mRNA levels between FBXW-7 and HES-1. Notch-1 mutations were associated with solid subtype (P = 0.02), advanced stage at diagnosis (P = 0.01), metastasis (P = 0.002), shorter relapse-free survival (RFS) (P = 0.008) and shorter overall survival (OS) (P = 0.006) compared with Notch-1 wild-type tumors. Notch-1 mutations were not an independent prognostic factor in the presence of histologic subtype and tumor stage. We demonstrated that Notch inhibition by Brontictuzumab reduced tumor cell proliferation and tumor formation in ACC patient-derived xenograft model harboring Notch-1 mutation.

Conclusion:
These data suggest that activated Notch pathway may be important to pathogenesis of ACC of the trachea and reveal Notch-1 as a target for therapeutic intervention in this subset of patients.

Background:
Testicular Germ-cell tumors are a common cancer in adults younger than 30 years-old. Extensive dissemination and high senitivity to chemotherapy are their principal characteristics. Chemotherapy is the standard of care, with an 80% probability of complete biochemical response with first line chemotherapy. Surgical resection of residual lesions after chemotherapy is indicated in some cases to rule out the presence of mature teratoma or viable tumor.

Method:
Retrospective chart review of patients with metastastic testicular Germ-cell tumors treated with chemotherapy and pulmonary metastasectomy from January 2006 to December 2014.

Result:
We found 56 cases with complete data for revision. Mean age was 25 years (16-48) Patients with lung metastases at diagnosis were 83.9%. All patients were treated with chemotherapy after initial orchiectomy. Preoperative serum tumor markers were negative in 44 patients (78%) Thoracotomy was performed in 48 cases (85.7%) and minimally invasive surgery in 8 cases (14.3%) Pulmonary wedge resection was performed in 52 patients (92.8%) and a lobectomy was required in 4 patients (7.2%) A R0 resection was achieved in 98.3%. Necrosis was reported in 25 cases (44.6%), mature teratoma in 17 (30.4%), viable germ-cell tumor in 13 patients (23.2%) and 1 case with seminoma (1.8%) All patients with viable tumor were offered postoperative chemotherapy. Median follow-up was 53.2 months (6-110). Median Overall Survival has not reached. Factors associated with improved survival were negative preoperative serum tumor markers and abscense of viable germ-cell tumor on resected specimens. Figure 1



Conclusion:
Removal of residual lesions after chemotherapy serves a double purpose, as an adjuvant treatment to chemotherapy allowing for “local” control of metastases and it also provides information about response to chemotherapy, with implications on prognosis and guiding postoperative treatment. In our cohort we demonstrate that despite a high proportion of viable tumors on surgical specimen, multi-modality treatment including lung metastasectomy is associated with prolonged survival

Background:
Programmed death-ligand 1 (PD-L1), is reported to serve as an indicator of prognosis in many malignant tumors. The aim of this study was to determine whether PD-L1 expression status in tumor cell can predict patient’s prognosis in esophageal squamous cell carcinoma (ESCC).

Method:
246 paraffin-embedded tissue samples were detected PD-L1 expression by immunohistochemistry from ESCC patients after surgery. And we statistically analyzed the association between expression of PD-L1 and clinicopathological factors and outcomes of survival.

Result:
The rate of positive PD-L1 expression was 24.4% (60/246) . Multivariate analysis indicated positive PD-L1 expression was associated with advanced TNM stage (P=0.009). The median of overall survival (OS) for patients with positive PD-L1 expression was similar to those with negative PD-L1 expression (Median OS, 52.4 vs. 56.4 months, P=0.466). However, in the subgroup analysis, the results indicated that the prognosis of patients with positive PD-L1 expression treated with adjuvant radiotherapy was significantly better than those with negative PD-L1 expression (Median OS, 84.4 vs. 36.0 months, P=0.046), while the OS of positive PD-L1 expression patients treated with adjuvant chemotherapy was poorer than those with negative PD-L1 expression although without significant statistical differences (Median OS, 21.8 months vs. 41.0 months, P=0.765) (Figure 1). Multivariate Cox regression hazards analysis revealed PD-L1 expression statue was not an independent prognostic factor (P=0.804) for entire cohort.Figure 1 Subgroup analysis for OS in ESCC based upon PD-L1 expression. (A) Subgroup of surgery alone; (B) Subgroup of surgery plus adjuvant chemotherapy; (C) Subgroup of surgery plus adjuvant radiotherapy; (D) Subgroup of surgery plus adjuvant chemoradiotherapy.



Conclusion:
Positive PD-L1 expression was likely to be more associated with malignant biological behavior of ESCC. PD-L1 expression was not a prognostic factor of OS for entire cohort, however, it is a prognostic factor in patients treated with postoperative adjuvant radiotherapy.

Background:
c-Met is reported to serve as a poor prognostic factor in many malignant tumors. Previous studies have suggested the involvement of c-Met in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients.

Method:
The expression of c-Met was immunohistochemically assessed in 180 surgically obtained tissue specimens. The correlation between c-Met expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with c-Met inhibitor in ESCC cell line.

Result:
There was no significantly correlated between c-Met expression and patients’ clinicopathological features. However, there was a significant difference in OS (median: 41.9 vs. 56.7 months; p= 0.001) between the high c-Met and low/negative c-Met expressing groups. In subgroup of patients with adjuvant radiotherapy, high expression of c-Met was correlated with poor disease prognosis (p= 0.002), while there was no significant correlation in patients with adjuvant chemotherapy. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor significantly inhibited the growth of an ESCC cell line with high c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor.

Conclusion:
The results of our study identified c-Met expression as an independent prognostic factor in ESCC and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with high c-Met expression.

Abstract not provided

Background:
To date the nodal status is considered one of the most important indicators of prognosis for resectable NSCLC. The latest edition of lung TNM does not include any changes to N descriptors, but several changing proposals are under evaluation: IASLC proposed a subclassification of pN1-N2 based on the number of nodal station involved (pN1a, pN1b; pN2a1, pN2a2, pN2b). The number of positive lymph nodes and the lymph node ratio were also proposed as prognostic indicators of resected NSCLC. The aim of this study was to compare overall survival (OS) and Disease Free Interval (DFI) of pN2a1 (“skip” metastasis) to pN1b and pN2a2-pN2b.

Method:
A retrospectively analysis of 155 patients who underwent a complete resection and a systematic lymph node dissection for T1/T2 N1-N2 NSCLC (VII TNM edition) between 2006 and 2010 was conducted. Patients who underwent induction therapies or extended resections were excluded. All patients were restaged with the new IASLC proposal. OS, DFI and risk factors of pN1b, pN2a and pN2b patients were analysed.

Result:
An overall mean number of 16 (DS 8,4) lymph nodes were resected: 7,18 (DS 4,2) from the hilum and 8,72 (DS 5,9) from the mediastinum. After restaging all cases with new IASLC proposal we observed: 48 (30,9%) pN1b, 26 (16,8%) pN2a1, 63 (40,7%) pN2a2 and 18 (11,6%) pN2b. With a median follow up of 93 months, the median overall survival of the entire cohort was 27 months. pN2a1 had a significant better overall survival when compared with the other three groups (p=0,042). 1, 3 and 5-year survival for pN1b, pN2a1, pN2a2 and pN2b were 75%, 90%, 81% and 71%; 46%, 53%, 37% and 24%; 24%, 45%, 26% and 19% respectively. A number of more than 5 positive lymph nodes and a lymph node ratio >50% were independent prognostic factors of a worse survival (p=0,004 and p=0,035).

Conclusion:
Our data supports the new IASLC proposal for the revision of N descriptors. Patients with skip lymph node metastasis (pN2a1) have a significant better prognosis compared both to other pN2 groups and to pN1b. Moreover, we confirmed the important prognostic value of the number of the involved lymph node, which should be considered as well in the next edition of the lung cancer staging system.

Background:
Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients are considered to be a heterogeneous population. The heterogeneity applies to tumor cells but to the microenvironment as well. Mounting evidence suggests that tumor infiltrating lymphocytes (TILs) are of clinical importance. Hence, we aimed to evaluate the role of the immune microenvironment as an immunoscore in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.

Method:
All patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital from 2005 to 2012 were retrospectively reviewed. Tissue microarrays were constructed by the surgical pathology specimens from primary lung tumors. For each specimen, we selected two cores from the tumor center (CT) and two cores from invasive margin (IM) region. Densities of immune cell subpopulations (CD3+, CD45RO+, and CD8+ TILs) were evaluated using immunohistochemistry with image analysis workstation (Vectra 3.0). Immunoscore is based on the numeration of two lymphocyte populations: CD45RO+ memory lymphocytes and CD8+ cytotoxic cells, quantified within the CT and IM. The immunoscore (I) provides a score ranging from I0 when low densities of both cell types are found in both regions, to I4 when high densities are found in both regions. The results were correlated with tumor recurrence and patient survival.

Result:
Of the eligible 357 patients, 288 patients with well-established lung tumor samples were obtained and included in the analysis. The median follow-up duration was 54.9 months (range, 23.9-132 months) for the living patients. The 5-year distant metastasis-free survival (DMFS) and overall survival (OS) rates were 26% and 34%, respectively. In univariate analyses, densities of CD3+ cells were associated with neither OS nor DMFS, whereas CD45RO+ cells in IM were prognostic for DMFS (P=0.02) and OS (P=0.05). Combining CD45RO and CD8+ TILs (CT plus IM), the immunoscore(I) significantly increased the prognostic impact. Of the 288 patients, there were 68 (24%) with I0, 64 (22%) I1, 58 (20%) I2, 48 (17%) I3, and 50 (17%) I4. Five-year DMFS and OS rates were 17% and 28% for the group with low immune score (N=190, I0-2), compared with 42% and 45% for the group with high immune score (N=98, I3-4), respectively (DMFS P<0.001; OS P=0.001). Multivariate analyses showed that the immunoscore had independent effects on DMFS (P<0.001) and OS (P<0.001).

Conclusion:
The immunoscore in NSCLC may provide powerful prognostic information, including the prediction of DMFS and OS, and thus facilitate clinical decision making regarding systemic therapy in patients with completely resected stage IIIA(N2) NSCLC.

Background:
Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients are a heterogeneous population, with 5-year survival rates ranging from 10% to 30%. The aim of this study was to investigate the relationship between the predominant subtype according to the new IASLC/ATS/ERS pathologic classification and prognosis in completely resected stage IIIA(N2) lung adenocarcinoma.

Method:
The medical records of 179 consecutive patients with completely resected stage IIIA(N2) NSCLC were reviewed between January 2005 and July 2012. According to the new pathologic classification, each tumor was reviewed using the comprehensive histological subtyping while recording the percentage in 5% increments for each histological component. Adenocarcinoma was divided into lepidic predominant, papillary predominant, acinar predominant, micropapillary predominant and solid-predominant. The predominant pattern was defined as the pattern with the largest percentage. To compare progression-free survival (PFS) and overall survival (OS) time between difference subtypes in lung adenocarcinomas, log-rank test was used for univariate analysis, and cox regression was used for multivariate analysis.

Result:
The median follow-up time was 42.7 months (range, 4.4–96.7months). The median PFS and OS time was 19.6 and 45.5 months, respectively. The 5-year PFS and OS rates were 16.4% and 34.6%, respectively. Patients with micropapillary and solid predominant tumors had poorer PFS (p=0.027) and OS (p=0.003) as compared to those with other subtypes predominant tumors. Micropapillary and solid predominant tumors were also significantly associated with an increased risk of locoregional recurrence (P=0.025), while not significantly associated with distant metastasis (P=0.21) than other subtypes predominant tumors. Multivariate analysis revealed that the new classification, chemotherapy, clinical N stage and LN ratio were independent prognostic factors for OS. Figure 1



Conclusion:
In patients with completely resected stage IIIA(N2) NSCLC, the predominant subtype according to new IASLC/ATS/ERS classification was an independent prognostic factor. It is valuable of screening out high risk patients to receive postoperative adjuvant therapy.

Background:
There is no large scale study of the initial surgery for patients with cN2 disease who received positron emission tomography (PET). We investigated the outcomes of initial surgery for patients with cN2 disease who had received PET, by conducting a multi-institutional retrospective study.

Method:
Clinical data for 143 patients who had cN2 disease and underwent initial surgery at 12 Japanese institutions in Thoracic Surgery Study Group of Osaka University (TSSGO) between January 2006 and December 2013 were collected. After reviewing all the data for eligibility, completeness, and consistency, 8 cases were excluded. The remaining 135 cases were feasible for analysis. Among these patients, 98 received PET and were analyzed.

Result:
The median follow-up was 56.5 months (2-110 months). The median age was 67 (35-80) years. There were 71 males and 27 females. The histology was adenocarcinoma (n=66), non-adenocarcinoma (n=33). The tumor location was the right upper lobe and left upper segment (n=66, 67.3%), and the others (n=32, 32.6%). Of 98 patients, 85 (86.7%) had clinical single N2 disease and 80 (81.6%) had no mode of spread lesion and 90 (91.8%) underwent lobectomy. The 5-year relapse free survival (RFS) rate and the 5-year overall survival (OS) rate for patients with cN2 were 34.6% and 46.6%. There were 24 patients (24.9%) with cN2pN0,1 and 74 patients (75.5%) with pN2. Of 74 patients with cN2pN2 disease, 42 (59.5%) had pathological single N2 disease and 40 (54.0%) underwent adjuvant chemotherapy. The 5-year RFS for the patients with cN2 in the cN2pN0,1 and cN2pN2 groups were 62.2% and 26.0%, respectively (p=0.0025). The 5-year OS for the patients with cN2 in the cN2pN0,1 and cN2pN2 groups were 74.8% and 40.0%, respectively (p=0.029). Moreover, we provided the following 3 criteria: primary tumor in right upper lobe or left upper segment, N2 disease with regional mode of spread, and patients who did not undergo pneumonectomy. 60 patients who fulfilled all of these criteria were regarded as specific group. The 5-year OS for the patients with cN2 in the specific group and non-specific group was 55.8% and 32.0%, respectively (p=0.024).

Conclusion:
Among patients with cN2 disease, those with pN2 disease were more in number in our study than in previous reports. Our patients with cN2pN2 had better survival compared with those in previous reports. In particularly, patients with clinical N2 disease in specific group have a favorable prognosis. An initial surgery may be considered as a treatment option for these patients.

Abstract not provided

Background:
Both cisplatin (CDDP)+S-1 and CDDP+pemetrexed (PEM) can be given at full systemic doses with thoracic radiotherapy (TRT) in locally advanced non-small cell lung cancer (NSCLC), and CDDP+PEM is one of the standard chemotherapy regimens in patients with advanced non-squamous (non-sq) NSCLC. This multicenter, randomized, open-label, phase II study (SPECTRA) compared the efficacy and safety of the two above-mentioned promising regimens combined with TRT in patients with unresectable locally advanced non-sq NSCLC.

Method:
Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. If the 2-year PFS rate is assumed to be 25% in the inferior therapy group and 15% higher in the superior therapy group of this study, the sample size needed for selection of the optimum treatment group at a probability of approximately 95% will be 51 cases/group with the Simon’s selection design. The sample size was set at 100 patients.

Result:
Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n=17 (33%)/n=17 (34%); stage IIIB, n=21 (40%)/n=20 (40%); ECOG PS of 1, n=14 (27%)/n=14 (28%); never smoker, n=12 (23%)/n=12 (24%); and adenocarcinoma, n=47(90%)/n=45(90%). Completion rate of TRT (60Gy) and chemotherapy (4 cycles) was 92%/98% and 73%/86%, respectively. Response rate was 60%/64%. Grade 3 or higher toxicities included febrile neutropenia (12%/2%), anorexia (8%/16%), diarrhea (8%/0%), esophagitis (6%/8%), pneumonia (4%/4%), neutropenia (38%/52%), anemia (8%/12%), thrombocytopenia (4%/6%), and hyponatremia (12%/12%). Grade 1 radiation pneumonitis was observed in 8 (15%)/2 (4%) patients on the basis of the data collected 30 days or less after the discontinuation of protocol treatment. No treatment-related death was observed. The data on PFS and overall survival are immature.

Conclusion:
Response rate was similar between the two arms. Toxicities were tolerable and manageable in both arms; however febrile neutropenia was more frequently observed in the CDDP+S-1 arm. We will present the updated safety data of this study at the conference. Survival data will be analyzed in late 2018.

Background:
CRT is a standard for patients with Stage III non-small cell lung cancer (NSCLC). Veliparib (V) is a potent, orally bioavailable PARP1/2 inhibitor that can delay DNA repair following chemotherapy or radiation induced damage. A phase 2 study indicated favorable efficacy of V vs placebo when added to P/C in advanced NSCLC (Ramalingam et al. Clin Cancer Res. 2016). Based on these results, a phase 1/2 trial was initiated to study the safety and efficacy of V/P/C-based CRT in the treatment of Stage III NSCLC.

Method:
Patients without prior NSCLC therapy suitable for definitive CRT received V plus C AUC 2 + P 45 mg/m[2] weekly + 60 Gy over 6-9 weeks. V was escalated from 60 mg BID to a maximum planned dose based on prior studies of 240 mg BID via 3+3 design with over-enrollment allowed followed by consolidation therapy of V 120 mg BID + C AUC 6 + P 200 mg/m[2] for up to two 21-day cycles.

Result:
Thirty-nine patients (median age 66; 14 male) have been enrolled to date into dosing cohorts at 60 mg (7), 80 mg (9), 120 mg (7), 200 mg (8), and a maximum planned dose of 240 mg (8). Median tumor volume at screening was 81 cc (16-555 cc). PK of V was dose proportional. CRT or V required dose reduction for 0 or 1 patient, respectively. Four (10%) patients discontinued study during CRT. No DLTs were observed and an MTD has not been identified. The most common any-grade AEs were esophagitis (23), nausea (22), fatigue (20), neutropenia (19), and thrombocytopenia (19). 27 SAEs occurred including 12 SAEs with reasonable attribution to V but outside the DLT window including G3/4 febrile neutropenia (2), G3 dehydration (1), G3 vomiting (1), G3 esophagitis (1), G3 radiation esophagitis (1), G3 esophageal stricture (1), G3 intractable N/V (1), G3 aspiration pneumonia (1), G3 radiation pneumonitis (1), G4 sepsis (1), and G5 sepsis during consolidation (1). Of 29 patients evaluable for tumor assessment, best response was CR (2), PR (22), SD (3), and PD (2).

Conclusion:
V/P/C-based CRT followed by V/P/C consolidation therapy is a tolerable regimen for the treatment of Stage III NSCLC. The RPTD for V during CRT is 240mg BID. A randomized placebo-controlled phase 2 extension of this study is planned. Clinical trial information: NCT02412371

Background:
Pathological staging (pTNM) after lung resection provides the most reliable data for staging non-small cell lung cancer (NSCLC) and predicting long-term survival. However, the survival rate of patients who undergo direct surgical treatment (pTNM) may differ from those who undergo lung resection after induction treatment due to locally advanced lung cancer (ypTNM). In this study we aim to compare the survival rate of pTNM versus ypTNM.

Method:
In this study, we retrospectively reviewed the prospectively recorded data of the patients undergoing surgery (segmentectomy or more) for NSCLC between 2006 and 2016. The patients were staged according to the 8th edition of TNM staging and divided into two groups. Group 1: patients who underwent direct surgical resection (n:450), Group 2: patients who received induction treatment before surgical resection for locally advanced NSCLC (n:345). We compared the survival rates and additional factors that affected the survival rates.

Result:
Postoperative histopathological investigation revealed ypT0N0 in 66 patients (complete response, group 2), stage 1 in 310 patients (group 1 n=211, group 2 n= 99) stage 2 in 223 patients (group 1 n=133, group 2 n= 90), stage 3 in 177 patients (group 1 n=100, group 2 n= 77), stage 4 in 19 patients (group 1 n=6, group 2 n= 13). Five year survival rate in all patients was 59,4% (group 1= 64,6%, group 2= 52,7%, p=0,001). Five year survival rate was 69,7% for complete response group. For patients with stage 1 disease survival rates were 81,9% for group 1 and 63,5% for group 2 (p=0,001). Patients with stage 2 had 5 year survival rates of 55,9% for group 1 and 45,9% for group 2 (p=0,11). Patients staged 3 and 4 had 5 year survival rates of 44,8% for group 1 and 34,4% for group 2 (p=0,10).

Conclusion:
This study revealed that survival rates varied between the patients who underwent direct surgery (pTNM) and the patients who underwent induction treatment before lung resection for locally advanced NSCLC. We recommend that the IASLC should examine the ypTNM stage in more detail in order to achieve more accurate results.

Abstract not provided

Background:
NVALT-11 randomized trial showed that PCI reduced the proportion of stage III NSCLC patients with symptomatic BM from 28 % to 5 % (Groen ASCO 2017). Here, we report on the toxicity.

Method:
We randomized between PCI or observation in radically treated stage III NSCLC. Primary endpoint: incidence of symptomatic brain metastases; secondary endpoints: OS, toxicity and quality of life.

Result:
Between 2009 and 2015 a total of 195 pts were registered, 175 were randomized, 87 received PCI and 88 pts were in the observation arm. Median follow up: 48.5 months (95% CI, 39-54). Neurological adverse events (AE) of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (18 vs. 2 pt; p< 10[-4]) and memory impairment (25 vs. 7 pt; p<10[-3]). No significant difference in G3-4 cognitive disturbance and memory impairment. Non-neurological AE of all grades that were more frequent in the PCI arm: alopecia (36 vs. 5 pt; p<10[-6]), fatigue (55 vs. 29 patients; p<10[-4]), nausea (30 vs. 15 patients; p=0.01), anorexia (6 vs. 0 patients; p=0.01) and dysphagia (11 vs. 2 pt; p=0.01). Of the G3-4 AE, only fatigue was significantly more present in the PCI arm (13 vs. 2 pt, p < 0.01). Scored as treatment-related, neurological toxicities of all grades that occurred more frequently in the PCI vs. the observation arm: cognitive disturbance (7 vs. 0 pt; p=0.01), dizziness (7 vs. 0 pt; p=0.01) and memory impairment (14 vs. 0 pt; p<10[-4]). No significant differences in G3-4 toxicities, with only one patient reporting severe cognitive disturbance in the PCI group. Scored as treatment-related, non-neurological toxicities of all grades that were more frequent in the PCI arm: alopecia (26 vs. 1 pt; p<10[-6]), fatigue (19 vs. 2 patients; p<10[-4]), nausea (16 vs. 0 patients; p<10[-5]), headache (19 vs. 1 pt; p<10[-5]), rash (8 vs. 0 pt; p<0.01) and vomiting (9 vs. 0 pt; p<0.01). No significant differences in G3-4 toxicities, with 3 patients reporting severe fatigue, 2 nausea and 1 vomiting, all in the PCI group. Overall Qol was worse in the PCI arm 3 months post-treatment, but was similar to observation thereafter.

Conclusion:
PCI related symptoms were mainly grade 1-2 memory and cognitive disturbances and fatigue. G3-4 toxicities were very rare. QoL was only temporarily affected by PCI. The side effects of PCI should be balanced against deteriorating BM symptoms and the lack of OS benefit (Groen ASCO 2017).

Background:
There are no clinically validated biomarkers to identify patients with locally advanced NSCLC who benefit from trimodality therapy (TMT) (i.e. neoadjuvant chemoradiation (NAT) followed by surgery). In this study, we evaluate radiomic (i.e. computer extracted imaging) features of tumor phenotype as potential predictors of pathological response.

Method:
123 patients with stage III NSCLC who received TMT were selected for this study. Of these, 33 patients including those with distant metastasis at presentation and those without baseline pre-NAT CT scans were excluded. Lung tumors were retrospectively contoured on 3D SLICER software by an expert reader. A total of 1542 radiomic features (textural and shape) were extracted from intra and peritumoral region using the MATLAB® 2016a platform (Mathworks, Natick, MA). A random forest (RF) machine classifier was trained with the most predictive features identified on the training set (n=45) and then validated on an independent test set (n=45). The primary endpoint of our study was pathological response defined as the percentage of the residual viable tumor.

Result:
90 patients with NSCLC were included for analysis with a median age of 64 years (38−88), and 54.4 % men. Tumor histology was predominantly adenocarcinoma (71.1%), stage IIIA (94.4%), with positive N2 nodes (91.1%). Pathological response was achieved in 36 (40%) patients; labeled responders (R) and the rest 54 (60%) were labeled non-responders (NR). No statistically significant difference was found in clinical characteristics. We identified five radiomic features (intratumoral and peritumoral textural patterns) predictive of pathological response (Area under Receiver Operating Characteristic (ROC) Curve = 0.7806, RF classifier). Figure 1



Conclusion:
Texture features extracted from within and around the lung tumor on CT images were predictive of pathological response to NAT. Additional validation of these quantitative image-based biomarkers is warranted for accurate early identification of responders who could be potentially spared surgery.

Background:
Response criteria for 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for thoracic malignancies include European Organization for Research and Treatment of Cancer (EORTC) criteria, Positron Emission tomography Response Criteria In Solid Tumors 1.0 (PERCIST), PeterMac Metabolic Visual Criteria and Deauville Criteria. It is unknown which criteria have the highest prognostic value in NSCLC.

Method:
Between 2004 and 2016, three NSCLC prospective trials included patients treated with radical radiotherapy (RT) or chemoRT with baseline and post-treatment FDG-PET imaging. For each patient, the four FDG-PET response criteria were reported retrospectively and blinded to outcome. Responses to therapy were categorized as complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD) or progressive metabolic disease (PMD) and correlated with subsequent survival using Cox proportional hazard models, c-statistic, r[2] and Akaike information criterion (AIC).

Result:
Eighty-seven NSCLC patients underwent FDG-PET before and after radical RT (n=7) or chemoRT (n=80). Follow-up FDG-PET scans were performed at a median of 89 days (range 47-123 days) after RT. After a median follow-up of 49 months, median survival after PET response imaging was 28 months. Both qualitative response criteria (PeterMac and Deauville) showed perfect agreement (kappa = 1.0). Both semiquantitative criteria (EORTC and PERCIST) showed almost perfect agreement (kappa = 0.96). All four response criteria showed statistically significant associations with overall survival. The PeterMac and the Deauville criteria showed stronger survival associations (AIC=357.9) compared to EORTC (AIC=362.3) and PERCIST (AIC=362.6). The two qualitative criteria also performed better in the distinction between CMR and non-CMR (HR = 1.9, CI 1.0-3.4, p=0.047) versus EORTC (HR=1.2, CI 0.6-2.3, p=0.566) and PERCIST (HR 1.2, CI 0.6-2.3, p=0.548). Only 1, 4 and 6 patients had SMD in respectively PeterMac/Deauville, EORTC and PERCIST. Figure 1



Conclusion:
The visual PeterMac and Deauville criteria showed stronger predictive capacity than EORTC and PERCIST criteria, especially for distinguishing CMR from non-CMR.

Background:
Micropapillary and solid subtypes of lung adenocarcinoma have significantly worse outcomes and survival after surgical resection for early-stage disease. These subtypes have recently been shown to have higher locoregional and metastatic progression after definitive stereotactic radiation therapy (SBRT) as well. However, the potential impact of histologic subtype on locally advanced disease treated with definitive concurrent or sequential chemoradiation (CRT) has not been previously explored. We sought to identify high-risk subtype patients treated with CRT, and compare their outcomes with those not known to have high-risk histologic subtypes.

Method:
We identified 249 consecutive patients with stage IIIA-B lung adenocarcinoma who had undergone CRT at our institution from 2008 to 2015. All patients had pathology reviewed by pathologists at our institution with subspecialty expertise in thoracic pathology. Twenty-five patients had elements of micropapillary and/or solid subtype on core biopsy, according to the 2015 World Health Organization classification. The remaining 224 patients were considered non-high-risk (8 patients had core biopsy with no high-risk subtypes identified; 216 patients either did not undergo core biopsy or did not have subtyping performed). Local, nodal, regional, and distant failure were estimated using cumulative incidence (CI) curves and compared using the log-rank test. Time to each event was measured from the date of diagnosis until the event of interest or the last follow-up visit.

Result:
With median followup of 19.7 months, there was a trend towards greater 2-year CI of local failure in the high-risk vs. non-high-risk group (40.7% vs. 26.7% p=0.060). The 2-year CI of nodal, regional, and distant failure in high-risk versus non-high-risk groups was 30.9% vs. 32.6% (p=0.576), 24.7% vs. 20.1% (p=0.468), and 63.9% vs. 59.8% (p=0.272), respectively, though statistical power was limited due to the small number of known high-risk patients.

Conclusion:
Though only a limited proportion of patients had demonstrated high-risk subtypes in this cohort, there was a trend towards earlier local failure in locally advanced adenocarcinoma patients treated with definitive concurrent or sequential chemoradiation, similar to what has been observed for early-stage tumors treated with SBRT. Hence, high-risk histologic subtype may be a prognostic factor for early treatment failure in locally advanced adenocarcinoma patients treated with CRT. We suggest that core biopsies, which are required for histologic subtyping, should be obtained more often in these patients, to allow for further study of the hypothesis that histologic subtype predicts outcomes after definitive chemoradiation.

Background:
The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating response to treatment. Selumetinib, an inhibitor of MEK, has been shown to enhance the effect of radiotherapy (RT) in preclinical studies.

Method:
Single-arm, single-centre, open-label phase I trial. Patients with stage III non-small cell lung cancer (NSCLC) not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms. Patients were recruited to a dose-finding stage (based on the Fibonacci 3+3 design; maximum number =18) followed by the recruitment of an expanded cohort (n=15). Oral Selumetinib (AZD6244, ARRY-142886) was administered at a starting dose of 50mg twice daily commencing 7 days prior to RT, then in combination with thoracic RT for 6-6.5 weeks (60-66Gy in 30-33 fractions). The primary objective was to determine the recommended Phase II dose.

Result:
From 06/10-02/15, 21patients enrolled. Median age 63 years (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%):IV 5(24%). Mean GTV 64cm[3] (range 0.8–223.7). In the dose-finding stage, 2 out of 6 patients experienced dose-limiting toxicities (DLT) but only one DLT (G3 diarrhoea) was attributable to treatment. Despite meeting criteria for escalation, trial management group elected to treat patients on the expanded cohort (n=15) at the starting dose. All 21 patients completed RT as planned and received induction chemotherapy. Compliance rate of Selumetinib was >80%. Common adverse events are listed-see table. There were 2 survivors (24 & 26months) at analysis. The median survival was 9.7 months and 2-year survival was 24%. The main cause of disease progression was distant metastases in 16/21 (76%).

Conclusion:
The combination of thoracic RT and Selumetinib is feasible and associated with an acceptable toxicity profile. However our efficacy results, based on 21 patients, suggest that this combination should not be pursued in a subsequent phase II trial.

Acute Toxicity (CTCAE v4.0) (during treatment and including up to 3 months post treatment)
Toxicity	Grade	N = 21 (%)
Acneiform rash	0 1 2 3	4 (19.04%) 7 (33.33%) 9 (42.86%) 1 (4.76%)
AST[1] increased	0 1 3	17 (80.95%) 3 (14.29%) 1 (4.76%)**
Diarrhoea	0 1 2 3	5 (23.81%) 13 (61.90%) 2 (9.52%) 1 (4.76%)*
GGT[2] increased	0 1 2 3	16 (76.19%) 2 (9.52%) 2 (9.52%) 1 (4.76%)
Haemoptysis	0 1	19 (90.48%) 2 (9.52%)
Maculo-papular rash	0 1 3	16 (76.19%) 4 (19.05%) 1 (4.76%)
Mucositis	0 1 2	18 (85.71%) 2 (9.52%) 1 (4.76%)
Nausea	0 1 2	11 (52.38%) 9 (42.86%) 1 (4.76%)
Radiation dermatitis	0 1 2 3	8 (38.10%) 7 (33.33%) 5 (23.81%) 1 (4.76%)
Radiation oesophagitis	0 1 2 3	3 (14.29%) 2 (9.52%) 15 (71.43%) 1 (4.76%)
Radiation pneumonitis	0 1 2	15 (71.43%) 0 6 (28.57%)
Late Toxicity (follow up from 3+ months onwards)
Toxicity	Grade	N = 21 (%)
Pneumonitis	0 1 2	16 2 (9.52%) 3 (14.29%)
Pulmonary fibrosis	0 1	19 2 (9.52%)
Radiation oesophagitis	0 2	19 (90.48%) 2 (9.52%)
* patient stopped drug on day 49 **patient stopped drug on day 29 abbreviations: 1) AST, Aspartate aminotransferase 2) GGT; Gamma-glutamyltransferase

Abstract not provided

Background:
Substantial evidence exists that quitting smoking after a cancer diagnosis can result in improved treatment efficacy and safety, decreased risk of recurrence and second primary cancers, and lower mortality. Based on this evidence, Cancer Care Ontario (CCO) implemented a smoking cessation program for new ambulatory cancer patients in Ontario’s 14 Regional Cancer Centres (RCCs) in 2014. Implementation is monitored centrally by CCO using performance indicators and monthly discussions with regional champions. Significant variation in implementation processes and performance metrics amongst RCCs highlighted a need for quality improvements.

Method:
Funding received from the Canadian Partnership Against Cancer enabled CCO to undertake a series of initiatives to enhance provider and patient education and to standardize processes. Based on program learnings and emerging evidence, the program model was revised from 5As (Ask, Advise, Assess, Assist, Arrange) to 3As (Ask, Advise, Act), and site-specific recommendations were provided to support consistency in implementation. Patient-facing materials, an on-line learning module, scripts and videos were developed to educate healthcare providers and patients on the health benefits of smoking cessation in order to improve rates of screening and referrals to cessation services. Importantly, two performance indicators have been included on CCO’s Regional Scorecard, which measures performance against targets and determines an RCC’s overall performance ranking within the province.

Result:
Performance on the Tobacco Use Screening indicator (proportion of new cancer patients screened for tobacco use) was 42.0% across Ontario in April 2015 when first included on the Scorecard. By March 2017, performance had improved to 62.7%, with significant improvements seen among the lowest-performing RCCs. The Accepted a Cessation Referral indicator (proportion of tobacco users who accepted referral to cessation services) improved only modestly from 19.7% in Q1 of 2016/17 to 23.4% in Q4. This indicator will be added to the Regional Scorecard starting in 2017/18. Both indicators are discussed at the quarterly performance reviews with the Regional Vice-Presidents responsible for cancer services. In 2016/17, lung cancer patients accounted for the largest percentage of current users of tobacco by tumour site (21.9%); in addition, almost a quarter of all patients accepting a referral (24.3%) were lung cancer patients.

Conclusion:
The CCO performance Scorecard is a strong driver of quality improvement. CCO is encouraged by regional enthusiasm to adopt the refined 3As model, and anticipates further improvements in the performance metrics, especially in the number of tobacco users who accept referral to cessation services.

Background:
The National Lung Screening Trial demonstrated that lung screening reduces lung cancer mortality. In our lung screening program, the incidence of lung cancer is a small percentage (2.3% (10/440)). A more common, treatable, and potentially overlooked condition in this population is nicotine addiction (70.2% smoking (309/440) in our program). It has been widely postulated that lung cancer screening provides a “teachable moment” for smoking cessation. Smoking cessation counseling has been integrated in our lung cancer screening program since 2014. The goal is to report outcomes of integrating smoking cessation in the lung screening program.

Method:
In our lung screening program, all scheduling is done by a single coordinator who is both a Nurse Practitioner and a Certified Tobacco Treatment Specialist (CTTS). A call to schedule the scan is done and initial basic tobacco cessation intervention is integrated into every call. Further follow up as in depth face-to-face counseling is offered at the point of the scan, by the coordinator or other CTTS. Tobacco cessation follow up may be further integrated into telephone calls to give patients screening results. Patients noted to be smoking at the time of the screen (n=103) were surveyed by telephone by a researcher to determine whether they had quit smoking, reduced, or made no changes. Further chart review yielded 107 additional patients unable to be reached by the researcher, but data regarding smoking was available from medical records.

Result:
Of the patients able to be contacted by telephone, 11.7% (12/103) quit smoking, 53.4% (55/103) had reduced the amount they were smoking, and 35.0% (36/103) had made no changes. Additional chart review yielded 107 patients screened and 14.0% (15/107) had documented cessation at least one year after screening.

Conclusion:
Integration of tobacco cessation counseling into our lung screening program led to an overall quit rate of 12.9% (27/210) and of those interviewed, 60.4% (55/91) of those who did not quit, reduced the amount that they smoked. While this may sound modest, this population is heavily addicted, and unaided cessation has poor success rates, often cited as less than 4%. This supports integration of cessation counseling as a potential model for improving smoking cessation in the lung screening population. Further work with integrating pharmacotherapy and more frequent regular follow up may yield even higher success rates.

Background:
Although the best way for smokers to avoid the health risks associated with smoking is to quit smoking altogether, for those who do continue to smoke the application of a harm reduction strategy could result in substantial reductions in mortality and morbidity. One such approach for continuing smokers would be to promote the substitution of alternative, less toxic means of delivering nicotine, assuming that these were proven to be less hazardous than tobacco smoking and did not cause any additional health risks. Electronic cigarettes, commonly called "e-cigarettes", represent a new stage in which nicotine is delivered in a method that simulates smoking but without involving a tobacco combustion process.

Method:
We measured levels of selected carcinogens and toxicants in aerosol generated from e‑cigarettes. Using in vitro systems, we studied toxicological effects of e-cigarette aerosol on bronchial epithelial cells. In a longitudinal within-subjects observational study, we assessed exposure to nicotine and selected carcinogens in cigarette smokers who switched to e-cigarettes. In a cross-sectional study, we compared exposure to nicotine and carcinogens among smokers of combustible cigarettes only, e-cigarette user, former smokers with long-term nicotine replacement therapy (NRT) use, and dual users of both combustible cigarettes and e-cigarettes.

Result:
Nicotine solutions used in e-cigarettes vary with respect to concentrations of toxicants. We identified a number of toxicants in e-cigarettes; however the levels of these toxicants were orders of magnitude lower than those found in cigarette smoke. In vitro studies showed that cell viability and metabolic activity were more adversely affected by conventional cigarettes than e-cigarettes. In longitudinal observational study of smokers, we found that after switching from tobacco to e-cigarettes nicotine exposure is unchanged while exposure to toxicants is substantially reduced. Long-term e-cigarette use, but not dual use of e-cigarettes with combustible cigarettes, is associated with substantially reduced exposure levels to carcinogens relative to smoking combustible cigarettes.

Conclusion:
Although it cannot be said that currently marketed e-cigarettes are safe, e-cigarette aerosol is likely to be much less toxic than cigarette smoke. The devices likely pose less direct hazard to the individual smoker than tobacco cigarettes and might help smokers quit smoking or reduce harm by smoking fewer cigarettes. The use of e-cigarettes as a harm reduction strategy among cigarette smokers who are unable to quit, warrants further studies. Further research is needed to evaluate long term effects of switching, including the health effects of continued use of e-cigarettes.

Background:
Lung cancer screening might be a ‘teachable moment’ for smoking cessation or conversely could provide a ‘license to smoke’. Such effects should be considered in the overall benefits and harms of screening. Existing evidence of the impact of screening on smoking is mixed.

Method:
A randomised controlled trial of a blood autoantibody test (EarlyCDT-Lung) for the early detection of lung cancer was conducted in 12,210 smokers and ex-smokers in Scotland, UK. The test allowed risk stratification for targeting of a chest X-ray and repeat CT scans. Sub-samples of positive test (n = 321), negative test (n = 361) and control (n = 350) participants completed questionnaires before screening, after receipt of blood test results and at 3, 6 and 12 months post-screening. They self-reported smoking point prevalence, attempts to quit, number of cigarettes smoked per day and the Heaviness of Smoking Index. Multi-level regression analyses, adjusted for confounders, explored differences in smoking over time between screened and control arms and between positive test, negative test and control groups.

Result:
Preliminary results show no statistically significant differences in smoking prevalence between the screened and control arms over time. There was a reduction in smoking prevalence of borderline statistical significance in the positive test group versus controls across all time points (OR 0.46, 95% CI 0.21-1.03). This difference reduced when assuming non-responding smokers were still smoking (OR 0.55, 95% CI 0.25-1.19). Significantly more smokers in the positive test group had recently attempted to stop smoking at 3 months compared to controls (OR 2.29, 95% CI 1.04-5.04). Positive test group smokers were significantly less likely to report smoking 20 or more cigarettes a day than controls across all time points (OR 0.32, 95% CI 0.14-0.69). Negative test group smokers were more likely to score moderate/high/very high on the Heaviness of Smoking Index compared to controls at 6 months. This difference was statistically significant before adjusting for confounders but the adjusted model was no longer significant (OR 2.51, 95% CI 0.90-6.97).

Conclusion:
There was no effect of lung cancer screening on smoking prevalence. The findings indicate a positive test result can be a teachable moment for smoking cessation. They also highlight the short term risk of heavier smoking after a negative test result. This is an important area for further research to ensure negative lung cancer screening test results do not inadvertently promote continued and heavier smoking.

Abstract not provided

Background:
The median age at diagnosis of lung cancer is 70 years. Older patients are often not prescribed standard therapy. Due to multiple competing causes of death, older patients often do not demonstrate a benefit in overall survival (OS). It is important to know which older patients would actually be candidates for aggressive therapy based on their prognosis, and to develop a simple prognostic model that can help clinicians determine individual prognosis.

Method:
Data on patients enrolled on 38 NCI-sponsored cooperative group clinical trials of advanced non-small cell lung cancer (NSCLC) from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise procedure with all potential predictors: age, sex, race, ethnicity (Hispanic or non-Hispanic), performance status, initial stage, BMI, and weight loss in the past 3/6 months. We derived a prognostic score using the estimated Cox PH regression coefficient in the training set. To assess the performance of our prognostic model, we calculated the area under receiver operating characteristic (ROC) curve of 1- and 2-year survival in the testing set.

Result:
The final analysis included 1454 NSCLC patients ≥70 years of age. These patients were randomly divided into a training set (n=962) and a testing set (n=492). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS=1) + 8 (if PS=2) + 11 (if initial stage=IV) + 4 (if weight loss). Patients were classified into three prognostic groups by tertiles: good (0-6), intermediate (7-14) and poor (≥15). The median OS in the three groups in the testing set were: 14.6 months (95% CI, 12.2-18.5); 12.2 months (95% CI, 10.7-14.4) and 7.0 months (95% CI, 5.6-8.9), respectively. Despite its simplicity, the present model had area under the 1-year and 2-year ROCs (0.63 and 0.68, respectively) that were higher than existing models.

Conclusion:
Male gender, poor performance status, distant metastases and weight loss immediately prior to diagnosis predict for poor OS in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC based on basic clinical characteristics that are part of the routine evaluation process for every patient with NSCLC.

Background:
Overall survival and in-hospital mortality in resectable non-small cell lung cancer (NSCLC) patients varies with race. Asian patients have a better overall survival compared with White and Black patients, however, the prognostic factors contributing to these differences are still under studied. The aim of this study was to identify race-specific prognostic factors of overall mortality and in-hospital mortality in resectable NSCLC patients.

Method:
Using the Surveillance, Epidemiology, and End Results Registry linked to Medicare claims between 1991-2010, 35,461 NSCLC patients who underwent pulmonary resection were extracted. Factors associated with in-hospital mortality and overall mortality stratified by Asian and White were analyzed by multivariable logistic regression analysis and multivariable cox regression analysis, respectively.

Result:
Factors associated with in-hospital mortality in Asian patients were age ≥ 80 years (adjusted odd ratios (OR~adj~)=5.8, 95% Confidence interval (CI)=1.59-21.23), stage III disease (OR~adj~=3.93, 95%CI=1.55-9.96), lower lobe lesion (OR~adj~=3.52, 95%CI=1.54-8.02), pneumonectomy (OR~adj~=11.12, 95%CI=2.61-47.34), postoperative pulmonary complication (OR~adj~=5.39, 95%CI=2.51-11.56), postoperative infections (OR~adj~=28.19, (95%CI=10.62-74.83), and intraoperative complication (OR~adj~=10.87, 95%CI=2.64-44.79). In White patients factors associated with in-hospital mortality were old age, male gender, higher comorbidity index, advanced stage, non-teaching hospital, lower hospital volume, pneumonectomy, preoperative radiotherapy, postoperative and intraoperative complications. Factors associated with overall mortality in Asian patients were age ≥ 80 years (HR~adj~=1.63, 95%CI=1.23-2.16), higher Elixhauser comorbidity index (HR~adj~=1.02, 95%CI=1.01-1.04), lower median income, stage (HR~adj~(95%CI) =1.89(1.41-2.54) for stage II, 2.19(1.69-2.83) for stage III, and 3.85(2.59-5.73) for stage IV versus stage I), non-teaching hospital, and receiving radiotherapy (HR~adj~=1.76,95%CI=1.35-2.30). In White patients, factors associated with overall mortality included old age, male gender, single status, higher comorbidity index and score, lower median income, higher stage, non-squamous cell carcinoma, higher tumor differentiation, location of tumor, lower hospital volume, pneumonectomy, no mediastinal lymph node dissection, and receiving chemotherapy or radiotherapy.

Conclusion:
Race specific differences in number and type of prognostic factors for in-hospital and overall mortality point at biological differences in the tumor as well as differences in treatment.

Background:
While most cancer therapies are associated with toxicities, a major component of cancer treatment is to reduce cancer-related symptoms and impairment of function. Assessing how well this goal is achieved is dependent on accurate assessments of baseline symptoms prior to initiation of therapy. The objectives of this study were to describe the symptom burden of treatment-naïve lung cancer patients and to examine demographic and disease factors that correlate with symptom severity.

Method:
Symptom data from 460 treatment-naïve patients with lung cancer were obtained using the validated MD Anderson Symptom Inventory via a 0-10 numeric rating scale. Descriptive statistics were used to summarize patient demographic and clinical characteristics. Differences in symptom severity, symptom interference and quality of life by disease stage and histology were examined using either t-test or ANOVA. Multiple linear regression analysis was performed using age, gender, tumor stage and histology to determine significant predictors of pain and shortness of breath.

Result:
The most severe symptoms were fatigue, disturbed sleep, distress, pain, shortness of breath, sadness and drowsiness. About 62% of patients had at least one moderate to severe (rated 5 or greater) symptom, while 48% had at least one severe (rated 7 or greater) symptom. Disturbed sleep, distress, shortness of breath, sadness, and drowsiness were reported to be severe by at least 16% of the patients. As expected, patients with advanced stage had significantly more severe symptoms. Patients with small-cell carcinoma reported the most severe pain and shortness of breath. Multiple linear regression analysis showed that stage was a significant predictor of pain severity while controlling for histology, age and gender. Patients with advanced stage had a pain level that was 1.2 higher than patients with early stage disease (95% CI= 0.5 – 1.8, p<0.001. For shortness of breath, both histology and stage were significant predictors of severe levels while controlling for age and gender. Patients with advanced stage had a shortness of breath level that was 0.9 higher than patients with early stage disease (95% CI= 0.4 – 1.6, p<0.001). Patients with small cell carcinoma had a shortness of breath level that was 1.5 higher than those with adenocarcinoma (95% CI= 0.35 – 2.6, p<0.01).

Conclusion:
In conclusion, as much as 62% of treatment-naïve patients with lung cancer reported at least one moderate-to-severe symptoms prior to initiation of cancer therapy. This high burden suggests that symptoms should be assessed routinely and tracked in parallel with cancer treatment.

Background:
Despite multiple efforts led by the National Cancer Institute (NCI) specific patient populations remained underrepresented in cancer clinical trials (CT). Therefore, we determined the representation of minorities, the elderly, and women in lung cancer CT in the past 16 years.

Method:
Clinicaltrials.gov was queried on December 31[st], 2016 for all completed therapeutic lung cancer trials from 2000 to 2016. Trials with recruitment outside of the U.S. were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER cancer prevalence. Geographic location was classified within the 5 major U.S. regions: Northeast, Southeast, Midwest, Northwest and Southwest.

Result:
Out of 320 CT, only 88 trials (27.5%) reported race/ethnicity comprising 11, 723 enrollees. Industry sponsored 65% of the trials. Non-Hispanic whites (NHW) were more likely to be enrolled in CT (EF 2.8%) than African Americans (AA) (EF 1.5%, p<0.001) and Hispanics (EF 2.1% p<0.03). Asian patients were well represented (EF 9.2 %). Distribution by race and sex is described on Table 1. Only 44 (50%) trials divided participants by age (<65 or ≥65 years). The representation of trial participants was heavily skewed towards the younger age group. Median age was 62 years and 8,440 (72%) participants were <65 years of age (p<0.001). Industry sponsored trials were less likely to enroll Hispanic patients than NCI sponsored trials (1.1% vs. 3.8%). African Americans were less likely to be recruited in first line trials compared to NHW (11% vs. 36%, p<0.0001). Underrepresentation of minorities was not affected by recruitment site geographic location.

Conclusion:
NHW were more likely to be enrolled in clinical trials than African American and Hispanics, independent of the recruitment site geographic location. Collaboration between investigators, NCI, industry, and the community is necessary to ensure broad access of unrepresented populations to clinical trials.

Race/Ethnicity	2000-2016 Trial Participants n/%	Enrollment Fraction %	2013 Lung Cancer Prevalence %
Non-Hispanic White	9,350 (79.8)	2.8	82.7
African American	638 (5.4)	1.5	10.6
Hispanic	314 (2.7)	2.1	3.6
Asian/PI	1083 (9.2)	8.7	3.1
Native American	75 (0.6)	N/A	N/A
Other	263 (2.2)
Sex
Female	4,571 (39)	2.0	55.2
Male	7,152 (61)	3.8	44.8

Abstract not provided

Background:
In recent years, clinical studies on screening for lung cancer have demonstrated an initial lung cancer detection rate of 0.8-2.2%, with a total of 2.4-4.7% in 34-78 months of follow up. The National Lung Screening Trial (NLST), which compared screening by LDCT to annual chest X-ray, showed a 20% decrease in mortality in the screened population. Transitional cell carcinoma of the bladder (TCC) has a high survival rate, and has similar risk factors to lung cancer. Thus, TCC patients may stand to benefit from lung cancer screening.

Method:
The SEER (Statistics, Epidemiology and End Results) database was used to determine the incidence, Person-years at risk and the average time to diagnosis of lung cancer in patients with localized TCC of the bladder (American Joint Committee on cancer, 6[th] ed., stages 0-1) in years 2000-2013. Cumulative Incidence rates were calculated and stratified by age, sex and county level smoking data.

Result:
Based on 88,564 patients with localized TCC (F:M ratio 1:3.3), the 5 year incidence of lung cancer was 3.16%, and 10 year incidence was 5.85%. among patients over 40 from counties with a high percentage of smokers, the 5 year incidence of lung cancer was 3.46%, and 10 year incidence was 6.64%. The median time until diagnosis of lung cancer was 3.89 years for men and 3.16 years for women for ages 60-79, the age group with the highest incidence. Figure 1



Conclusion:
Incidence of lung cancer is high in localized TCC patients and comparable to results seen in the high risk groups currently being screened. Early stage TCC patients may therefore stand to gain from lung cancer screening, and should be considered as potential screening candidates.

Background:
Epidemiological studies commonly use data from clinical (i.e. medical records) and administrative (i.e. claims data) datasets for the purposes of exploratory analyses, as well as clinical and quality reporting, benchmarking, risk adjustment, and machine learning. Validity is contingent on accurate and detailed reporting of data, demanding robust methodological validation.

Method:
Single centre retrospective comparative study assessing completeness and agreement (kappa-statistic (κ)) of data reporting for key prognostic variables across three independent data sources, among patients with lung cancer. The study population was formed by random selection of patients from an Australian single centre prospective study. Prospectively collected research study-data (SD) was extracted, and then compared to data extracted from individual patient medical records (MR) as well as International Classification of Diseases (ICD) coding from administrative data (AD).

Result:
The study population included 10% of patients from an Australian lung cancer cohort (n=111/1090), and represented the overall cohort in terms of patient demographics and disease characteristics. Prognostic data for stage, comorbidities, smoking history, performance status, and weight loss at diagnosis, was reported for >96% of patients in SD. Comparatively, AD did not report any prognostic data for 42% (47/111) of patients treated in ambulatory settings, and indeed when reported was grossly inaccurate. By way of examples, according to AD, 23% of patients had ≥1 comorbidity versus 68% by MR and 64% by SD; 38% had positive smoking history versus 78% by MR and 81% by SD; 2% had respiratory comorbidity versus 28% by MR and 37% by SD. Similar patterns were observed for other comorbid conditions. Complete TNM staging was captured in only 45% of MR at the time of first treatment, although with good concordance with SD (κ=0.9, 95%CI 0.7, 1.0). Equally when factors were documented in MR they were reasonably concordant with SD: smoking status (completeness 96.4%, κ=0.9, 95%CI 0.8, 1.0), performance status (completeness 82.0%, κ=0.5, 95%CI 0.4, 0.7) and weight loss (completeness 71.1%, κ=0.3, 95%CI 0.1, 0.5).

Conclusion:
Poor capture of factors (either omission or inaccuracy) limit the potential contribution of both MR and AD for use in clinical, epidemiological, and machine learning research – particularly when being utilised to derive diagnostic, prognostic and classification systems. Use of this data for purposes other than intended may misinform estimates of comorbidity disease burden and fail to appropriately adjust for competing mortality risks in models that inform outcomes reporting and ensuing policy decisions.

Background:
Mutations of epidermal growth factor receptor (EGFR) gene have been proved as the strongest predictor of response to EGFR-tyrosine kinase inhibitor (TKI) treatment in NSCLC. Currently, 7 most common somatic mutations of EGFR have been reported, among which, L858R and exon 19 deletion theoretically confer sensitivity to EGFR TKIs, other primary EGFR mutations may confer resistance. The EGFR mutation profile showed significant geographical differences (about 35% in East-Asia and 10% in Caucasian population) but very limit data have been reported from China. In addition, we carried liquid biopsy and next generation DNA sequencing analysis on 180 samples from NSCLC patients. We hereby reported the mutation profile EGFR gene in a large scale, real world cohort of 2,666 Chinese NSCLC patients.

Method:
From January 2016 to June 2017, 7 primary EGFR mutations (L858R, Exon 19 del, G719X, L861Q, Exon 20 ins, S768I and T790M) were assayed in tumor tissue (paraffin-embedded or fresh) of 2,666 Chinese patients with NSCLC by a commercial TaqMan PCR kit (Human EGFR Gene Mutations Detection Kit（ACCB）). For liquid biopsy analysis, cell-free DNA is extracted from plasma, a panel of 96-targeted genes was assayed, and genomic alterations in cancer-associated somatic variants are analyzed by massively parallel sequencing.

Result:
Among the 2,666, 1,601(45.9%) were female and 1,447(54.1%) were male, 2,446 (91.7%) had adenocarcinoma (ADC) and 220(8.3%) had squamous carcinoma (SC).The median age of patients was 63 yr (range 17yr-91yr). The detailed EGFR mutation profile was shown in Table 1, the overall incidence of EGFR mutation was 1,319(49.5%). Compare to female patients, male patients showed significant lower rate of EGFR mutation (67.2% vs. 34.6%, p<0.01). More than 50% of patients with ADC showed EGFR mutation while the rate was only 10% in patients with SC. Exon 19 del and L858R, 2 markers for potential better response of TKI, account for the vast majority of all the EGFR mutations. We found the mutation profiles from samples analyzed by NGS is similar to those analyzed by PCR method.

Conclusion:
In Chinese NSCLC female patients with lung adenocarcinoma, exon 19 del and L858R represented more than 90% of the total EGFR mutations, thus, for those whose EGFR status was unable to be determined, direct TKI treatment many has an odd of 60% to benefit the patients. About 5% of SC patients also showed exon 19 del and L858R mutation which means they could be subjects for TKI treatment.

Background:
As the lung cancer treatment landscape evolves, it is important to understand changes in care and outcomes of patients with NSCLC. SCAN-LEAF objectives include describing NSCLC disease, treatments and health outcomes in Scandinavia (Denmark, Norway and Sweden). The present analyses examined treatment proportions and temporal trends in overall survival, drawing on national registry data.

Method:
NSCLC patients diagnosed 2005-2013 (follow-up until 2014) were included in the present analyses of this retrospective longitudinal cohort study. Patient characteristics and treatment described included demographics, disease stage at initial diagnosis [resectable: I-IIIA; locally advanced: IIIA-B (radiation therapy within 3 months); advanced: IIIB (no radiation therapy within 3 months)-IV], histology, non-drug treatment (surgery and radiation: present analyses include Norway and Sweden 2008-2014 only), and survival. Overall survival (OS) (%+95% CI) was calculated 1, 3, and 5 years post-diagnosis, by stage, and by diagnosis year.

Result:

Table 1. Proportion NSCLC patients from Denmark, Norway and Sweden diagnosed during 2005-2013 who survived 1, 3 and 5 years after diagnosis, by stage and calendar year of diagnosis.
Stage at diagnosis & Calendar year of diagnosis	% survived 1-, 3- and 5-years after NSCLC diagnosis
	1-year	3-year	5-year
Resectable disease
Overall	81.0% (80.4%, 81.6%)	56.8% (55.9%, 57.7%)	43.5% (42.5%, 44.6%)
2005	74.7% (72.5%, 77.0%)	51.0% (48.5%, 53.6%)	40.0% (37.4%, 42.5%)
2006	77.0% (74.8%, 79.2%)	53.3% (50.7%, 55.9%)	42.3% (39.7%, 44.8%)
2007	78.6% (76.6%, 80.7%)	55.0% (52.5%, 57.5%)	43.5% (41.1%, 46.0%)
2008	80.6% (78.6%, 82.5%)	56.4% (53.9%, 58.8%)	44.2% (41.7%, 46.7%)
2009	79.7% (77.7%, 81.7%)	57.4% (55.0%, 59.8%)	45.8% (43.3%, 48.2%)
2010	81.4% (79.6%, 83.2%)	59.1% (56.8%, 61.4%)
2011	83.1% (81.4%, 84.7%)	61.2% (59.0%, 63.4%)
2012	85.5% (84.0%, 87.0%)
2013	84.2% (82.7%, 85.8%)
p-value trend	<0.0001	<0.0001	0.0008
Locally advanced disease
Overall	52.0% (51.0%, 53.0%)	18.4% (17.5%, 19.3%)	10.8% (9.9%, 11.6%)
2005	45.7% (42.4%, 49.0%)	13.9% (11.6%, 16.2%)	7.8% (6.1%, 9.6%)
2006	45.7% (42.3%, 49.1%)	15.4% (12.9%, 17.8%)	10.7% (8.6%, 12.9%)
2007	51.5% (48.2%, 54.7%)	18.6% (16.0%, 21.1%)	11.0% (9.0%, 13.1%)
2008	50.0% (46.7%, 53.3%)	17.0% (14.5%, 19.4%)	10.3% (8.3%, 12.3%)
2009	50.9% (47.8%, 54.0%)	19.8% (17.4%, 22.3%)	12.9% (10.8%, 15.0%)
2010	51.1% (48.1%, 54.1%)	18.9% (16.5%, 21.2%)
2011	55.9% (53.1%, 58.7%)	21.2% (18.9%, 23.5%)
2012	57.0% (54.2%, 59.9%)
2013	56.1% (53.2%, 59.0%)
p-value trend	<0.0001	<0.0001	0.0021
Advanced disease
Overall	26.2% (25.7%, 26.6%)	6.3% (6.0%, 6.6%)	3.4% (3.2%, 3.7%)
2005	24.4% (23.1%, 25.8%)	6.3% (5.5%, 7.0%)	3.5% (2.9%, 4.1%)
2006	24.2% (22.8%, 25.5%)	6.1% (5.4%, 6.9%)	3.4% (2.8%, 4.0%)
2007	25.7% (24.4%, 27.0%)	5.9% (5.2%, 6.6%)	3.1% (2.6%, 3.7%)
2008	25.0% (23.7%, 26.3%)	6.0% (5.3%, 6.7%)	3.3% (2.8%, 3.9%)
2009	26.5% (25.0%, 28.0%)	6.9% (6.0%, 7.8%)	3.9% (3.2%, 4.5%)
2010	26.3% (24.9%, 27.7%)	7.0% (6.2%, 7.8%)
2011	27.4% (26.1%, 28.8%)	6.2% (5.4%, 6.9%)
2012	28.1% (26.7%, 29.5%)
2013	27.9% (26.6%, 29.3%)
p-value trend	<0.0001	0.2480	0.5359

66,012 NSCLC patients were diagnosed during 2005-2013 in Scandinavia (53.6% male, mean age 68.9 years); diagnosis stage: resectable (26%), locally advanced (15%), advanced (59%). In Norway and Sweden, surgery was performed on 58.5%, 9.9% and 1.9% of patients at resectable, locally advanced and advanced stage, respectively; radiation therapy in 28.0%, 58.0% and 30.4%, respectively. 1-yr OS gradually and significantly improved by calendar year of diagnosis for all disease stages. At 3 and 5 years post-diagnosis, OS was positively and significantly associated with calendar year of diagnosis for patients with resectable and locally advanced, but not advanced disease (Table 1).

Conclusion:
These analyses showed modest improvements in survival for patients with earlier stage disease over time. However, the majority of patients were diagnosed with advanced stage disease for which no improvement in temporal trends of survival was found, beyond one year post-diagnosis. This suggests an unmet need for effective treatments still remains, particularly for patients with advanced disease.

Abstract not provided